For years, mitochondrial dysfunction has been a cornerstone of exhausted T cells but exactly how metabolic stress leads to permanent transcriptional changes was unknown. This new study demonstrates a decisive molecular bridge linking mitochondrial stress to long lasting T cell dysfunction.

How T cells lose their energy

When mitochondria in CD8⁺ T cells become depolarised, the cells increase proteasome activity, a process that selectively degrades mitochondrial haemoproteins. This releases excess regulatory haem, which does not remain a byproduct but instead acts as a signalling molecule.

Haem translocates to the nucleus, where it binds and destabilises the transcription factor Bach2. This relieves repression of Blimp1, a master regulator of terminal exhaustion, locking T cells into a dysfunctional state and eroding their stem-like potential.

Mechanistically, the researchers identified CBLB as a driver of mitochondrial protein ubiquitination and PGRMC2 as a chaperone that enables nuclear haem transport.

A metabolic switch offers a treatment path

“This pathway explains how energy failure becomes immune failure,” said Professor Ping-Chih Ho, senior author of the study. “We uncovered a metabolic signalling switch that converts mitochondrial stress into a permanent transcriptional decision.”

Importantly, the research shows that this axis is actionable. Transient low-dose bortezomib treatment during CAR T cell manufacturing dampens proteasome-driven haem signalling, reduces exhaustion-associated programmes and promotes durable epigenetic reprogramming towards a memory-like state.

“Our last paper identified mitochondrial damage as the cause of T cell failure and this one reveals the molecular switch behind it and how to turn exhaustion off. For a long time, mitochondrial dysfunction was an observation without a clear mechanistic explanation,” said Y Xu, first author of the study. “Discovering that regulatory haem acts as the signalling mediator was unexpected and it gives us a tangible way to intervene.”

Data from patients with B-ALL reinforce the clinical significance of the findings. CAR T cells exhibiting high proteasome activity were associated with poorer therapeutic outcomes, highlighting the potential impact of targeting this pathway to improve treatment durability.

Redefining T cell exhaustion

The study reframes T cell exhaustion not merely because of chronic antigen stimulation but as the result of a dysregulated metabolic signalling circuit. By identifying a proteasome-guided haem pathway that dictates immune cell fate, the research opens new areas of study for optimising adoptive cellular immunotherapy, particularly CAR T approaches where long-term persistence is still a clinical challenge.

The findings may also help scientists design interventions to maintain T cell function, improve anti-tumour responses and ultimately enhance patient outcomes in a range of cancers.

How cancer hijacks lung repair

When breast cancer spreads to the lungs, it damages the tiny air sacs needed for breathing. Under normal circumstances, the lung responds quickly to repair this injury. However, the researchers found that cancer cells can manipulate this process.

Instead of allowing repair to complete, the tumour cells keep the lung locked in a prolonged state of healing. This leads to chronic inflammation and creates an environment that supports tumour growth.

Specialised cells known as alveolar type II cells, which typically help regenerate lung tissue, appear to play a central role in this process. In the presence of cancer, these cells begin releasing signals that encourage tumours to expand.

“The lung is doing what it is designed to do and that is to clear debris and repair damage,” said Dr Jessica Christenson, first author of the study and an instructor in the Department of Pathology at CU Anschutz. “But in this case cancer cells are taking advantage of that repair response.”

A harmful feedback loop

The team discovered that a two-way communication develops between cancer cells and lung cells. Tumour cells activate the lung’s repair mechanisms, while lung cells in turn release substances that further fuel cancer growth.

This feedback loop allows metastatic tumours to establish themselves and continue expanding within the lungs.

Existing drug shows promise

To explore whether this process could be disrupted, the researchers tested roflumilast, an anti-inflammatory drug already approved for treating chronic obstructive pulmonary disease.

In mouse models of metastatic breast cancer, the drug slowed tumour growth and reduced the size of lung tumours. Rather than directly killing cancer cells, roflumilast appeared to work by altering the lung environment so that it was less supportive of tumour development.

“This suggests a new strategy for treating metastatic cancer,” said Dr Jennifer Richer, senior author of the study and Professor of Pathology at the CU Anschutz Cancer Center. “In addition to targeting cancer cells themselves, we may also be able to target the environment that allows them to thrive.”

Why the findings matter

Breast cancer becomes significantly harder to treat once it spreads beyond the breast, with the lungs among the most common sites of metastasis. Around one third of patients with metastatic breast cancer develop tumours in the lungs, where treatment options remain limited.

Because roflumilast is already approved for another condition, researchers believe it could potentially be repurposed more quickly than completely new drugs.

Next steps towards the clinic

The team will now investigate how roflumilast might be combined with existing treatments such as chemotherapy or immunotherapy. They are also exploring inhaled versions of similar drugs that could deliver treatment directly to the lungs.

“We are very excited to translate these findings to the clinic and evaluate roflumilast as a treatment for patients with triple-negative breast cancer to prevent recurrence in the lungs,” said Jennifer Diamond, MD, Professor of Medical Oncology, Medical Director of the Cancer Clinical Trials Office at the CU Anschutz Cancer Center and a collaborator on the project.

Their research is the first study to combine genome sequencing with cellular reprogramming to pinpoint the causative mutation and explore how it drives disease.

Unusual symptoms point to unknown condition

The discovery began when clinicians identified a family in which teenage members showed signs typically associated with progeria syndromes, including premature greying of hair. However, the patients also exhibited symptoms not usually seen in such conditions.

“Our collaborator identified a family of patients whose teenaged members had whitening hairs and other characteristics associated with premature ageing conditions known as progeria syndromes,” said Director of the Center for Neurologic Diseases at Sanford Burnham Prebys and a senior author in the study, Dr Su-Chun Zhang. “Cognitive functions are often well preserved in these conditions, however, so it was clear from the patients’ progressive loss of motor skills and neurological and intellectual deficits that this was an unknown disease.”

Pinpointing a genetic cause

Using genome sequencing alongside mapping techniques for recessive traits, the researchers traced the condition to a mutation in the IVNS1ABP gene. This gene encodes a protein known to bind influenza virus components but had not previously been linked to ageing or neurological disease.

“Relatively little research has been done on this gene and protein, and no one has ever linked them to the biology of ageing, premature ageing diseases or neuropathy,” said Staff Scientist at Sanford Burnham Prebys and first author, Dr Fang Yuan. “It was a mystery in many ways and one we were determined to solve.”

The scientists studied brain organoids derived from patients suffering from a newly discovered genetic disease. These organoids had a more disorganised structure and fewer properly patterned developing nerve cells than healthy controls, suggesting impaired brain development. Credit: Fang Yuan, Su-Chun Zhang, Sanford Burnham Prebys.

Stem cell models reveal cellular damage

To understand how the mutation affects cells, the team reprogrammed skin cells from patients into induced pluripotent stem cells (iPSCs) and then into neural progenitor cells. These cells retained the genetic mutation, allowing detailed study in the laboratory.

“Under the microscope, we found that the patient-derived cells with the mutation grow much slower compared to the control group reprogrammed from a sibling without the disease,” said Zhang.

Further investigation showed that the affected cells had entered cellular senescence, a state in which cells stop dividing. Researchers identified multiple markers of DNA damage along with increased levels of a gene linked to this process.

“To narrow in on what was causing these cells to become senescent, we ran follow-up experiments showing that DNA damage was occurring during cell division and we saw that it could be severe enough to cause cell death,” said Yuan.

Faulty cell division mechanism uncovered

Although the IVNS1ABP gene had no known direct role in cell division, the team found evidence that it interacts with proteins involved in a key structural component of cells, called actin.

“During cell division, the actin filament needs to form an anchoring structure and it usually forms a very round and even ring structure,” said Zhang. “But in the mutant cells, the altered actin forms a shrunken and irregularly shaped ring so cells are not pulled apart in a symmetrical way and suffer damage.

“When these actin dynamics are altered, the cell cannot perform cell division at the right time and in the right place,” Yuan added.

Hope for future treatments

Encouragingly, the researchers found that treating the cells with compounds that stabilise actin structures improved normal cell division.

“This research highlights the potential of using cellular reprogramming and patient-derived stem cell models to study rare and unknown diseases,” said Zhang.

The researchers have demonstrated that correcting certain steps in the molecular processes can repair some of the cellular defects – at least in the lab-grown cell models.

They emphasised, however, that further studies using an animal model are needed to confirm the findings but the work already highlights the power of this approach for identifying new diseases and exploring potential treatments.

Long COVID, also known as post-COVID syndrome, is estimated to affect more than 10 percent of people following infection with SARS-CoV-2. The condition presents a wide range of symptoms, including extreme fatigue, post-exertional malaise and pain and cognitive difficulties often described as ‘brain fog’. Despite its prevalence, the biological mechanisms behind Long COVID have been poorly understood for some time.

Antibodies that transfer symptoms

In the study, researchers focused on immunoglobulin G, or IgG, a major class of antibodies found in the blood. They extracted IgG from 34 Long COVID patients and injected it into mice. Subsequently, the animals developed persistent pain-like hypersensitivity that lasted for at least two weeks.

More notably, IgG collected from the same patients two years later produced the same effect when introduced into mice.

“This finding suggests that the underlying disease mechanism may persist long after the initial infection, potentially explaining why many patients experience long-term symptoms,” said co-study lead Professor Niels Eijkelkamp.

Laboratory work at the Center for Translational Immunology. Credit: UMC Utrecht.

Distinct biological subgroups

To further investigate, the researchers analysed blood samples from Long COVID patients and identified distinct subgroups based on markers linked to brain injury and immune system activity. These included GFAP, NFL and interferon-β. Each subgroup showed unique molecular patterns in large-scale protein analyses.

When autoantibodies from these different groups were tested in mice, they produced varying symptom patterns.

“This finding supports the idea that Long COVID is not a single condition but a heterogeneous disease with different biological drivers,” said co-study lead and Principal Investigator at Amsterdam UMC, Jeroen den Dunnen.

A landscape of autoimmunity

The study also revealed that Long COVID patients have elevated levels of autoantibodies targeting a wide range of the body’s own proteins. These include proteins involved in immune regulation, nerve signalling and metabolism. Many of these autoantibodies were found to persist for years and differed across patient subgroups.

The researchers noted similarities with other conditions such as fibromyalgia, where patient-derived antibodies can also induce symptoms in animal models, suggesting shared immune pathways.

Towards targeted treatments

While the study has limitations, including its relatively small size, single-centre design and use of pooled samples, it provides strong evidence that IgG autoantibodies may actively contribute to Long COVID symptoms.

The findings also point towards new treatment approaches that could be designed to remove or neutralise harmful antibodies, such as immunoadsorption, plasmapheresis or targeted immunotherapy. All of these could offer relief to patients, particularly if tailored to specific biological subtypes.

Now, a new study from researchers at First Hospital of Jilin University suggests that machine learning could accelerate the discovery of novel treatments, identifying antimicrobial peptides (AMPs) with potential to treat UC.

AI-driven screening discovers promising peptides

Antimicrobial peptides are naturally occurring components of innate immunity that have both antimicrobial and immunomodulatory properties. Traditionally, discovering new AMPs requires labour-intensive screening and experimental testing. In the study, Miao and colleagues developed a machine-learning pipeline combining peptide prediction models with genetic algorithms to analyse structural and physicochemical properties of over 6,000 potential candidates. The study highlighted 22 sequences that looked promising.  

Five peptides were synthesised for laboratory testing. Among them, a peptide named LR, after its N- and C-terminal residues, showed the most favourable balance between antibacterial activity and low cytotoxicity. In vitro experiments demonstrated that LR had strong bactericidal effects against pathogenic bacteria including Escherichia coli and Staphylococcus aureus, while maintaining good biocompatibility, showing minimal toxicity and low haemolytic activity compared with other candidates.

Lead peptide reduces colitis in mice

To test its therapeutic potential, LR was administered to mice with dextran sulphate sodium (DSS)-induced colitis. Treatment led to substantial improvements in disease severity, including reduced body weight loss, improved disease activity index (DAI) and less colon shortening. Histological analysis showed reduced mucosal damage and decreased infiltration of inflammatory cells. Primarily, LR treatment produced stronger effects than both the standard anti-inflammatory drug 5-aminosalicylic acid and the antibiotic ciprofloxacin in this model.

AMP, antimicrobial peptide; DSS, dextran sulphate sodium; ZO-1, zonula occludens-1. Credit: By Hui Miao, Ziwei Wang, Pengfei Cui, et al.

Reducing inflammation and repairing the gut barrier

Further analyses revealed that LR suppressed inflammatory responses. Levels of pro-inflammatory cytokines such as tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were markedly reduced after treatment. Simultaneously, the peptide helped restore intestinal barrier integrity. The expression of tight junction proteins ZO-1, claudin-1 and occludin was significantly increased, suggesting improved epithelial barrier function. These results show that LR may exert therapeutic effects both by reducing inflammation and strengthening the intestinal mucosal barrier.

Shaping the gut microbiome drives therapeutic effects

The researchers also examined LR’s impact on gut microbial communities. Sequencing of faecal microbiota revealed that treatment reshaped microbial composition in mice with colitis. The abundance of the beneficial bacterium Akkermansia muciniphila, a species linked to improved gut barrier function and reduced inflammation, increased significantly. Supplementation with A. muciniphila alone partially alleviated colitis symptoms, suggesting that microbiota modulation contributes to LR’s therapeutic effect. LR selectively inhibited pathogenic bacteria while sparing A. muciniphila, highlighting a microbiome-friendly antimicrobial profile.

Possible future therapies

The study demonstrates how integrating computational screening with experimental validation can identify stable and selective AMPs with anti-inflammatory activity in UC. While more research is needed to assess long-term safety and applicability to humans, the findings highlight a new strategy for developing microbiota-friendly therapeutics for inflammatory bowel disease.

Glioblastoma is famously difficult to treat, with most patients surviving less than 18 months after diagnosis. Standard approaches such as surgery, radiotherapy and chemotherapy provide limited benefit and the disease often returns.

Protein found to drive tumour behaviour

The research demonstrates that CD47 actively supports tumour growth, movement and invasion into surrounding brain tissue.

“We’ve known for some time that CD47 acts as a kind of ‘don’t eat me’ signal that helps cancer cells hide from the immune system,” said Dr Nirmal Robinson, Senior Research Fellow at the University of Adelaide and a senior author of the study. “What we’ve discovered is that CD47 is doing much more than that; it’s actually driving the cancer’s ability to spread and grow.”

Researchers found that CD47 is especially concentrated at the invasive edges of glioblastoma tumours, which are the areas responsible for spreading into healthy brain tissue. Higher levels of the protein were also linked to significantly poorer survival outcomes in patients.

Blocking CD47 slows cancer progression

Working alongside Professor Stuart Pitson’s team, scientists used laboratory experiments and animal models to investigate the effects of removing or blocking CD47. They found this approach significantly reduced tumour cell proliferation, migration and invasion.

In some cases, tumours lacking CD47 grew more slowly and survival time in models nearly doubled. Notably, these effects occurred even without the presence of immune cells, confirming that CD47’s tumour-promoting role extends beyond immune evasion.

Key molecular pathway uncovered

The team also identified a partner protein, ROBO2, which operates downstream of CD47 and contributes to tumour growth and spread. Further investigation revealed that CD47 protects ROBO2 from being broken down inside the cell.

This protection occurs because CD47 sequesters another protein, ITCH, which would otherwise mark ROBO2 for destruction.

“Essentially CD47 is shielding ROBO2, allowing it to accumulate and drive tumour progression,” said Dr Ruhi Polara, Research Associate at the University of Adelaide who also led the research alongside Dr Robinson. “When we remove CD47, ROBO2 is degraded and the cancer cells lose their ability to grow and invade effectively.”

New directions for treatment

The discovery of the CD47-ITCH-ROBO2 pathway provides a new understanding of how glioblastoma behaves and opens up potential avenues for treatment. Although therapies targeting CD47 are already being trialled in other cancers, they have shown limited success in glioblastoma.

The researchers suggest that directly targeting this newly identified pathway, or interfering with the stabilisation of ROBO2, may be more effective.

“By understanding this mechanism we now have new targets to explore,” Dr Polara said. “This could lead to the development of therapies that specifically block the tumour’s ability to spread, which is one of the biggest challenges in treating glioblastoma.”

Rethinking cancer biology

The findings also highlight the importance of looking beyond immune system interactions when developing cancer therapies.

“This work changes how we think about CD47,” said Dr Robinson. “It’s not just an immune checkpoint; it’s a central regulator of tumour biology in its own right.”

Researchers say further work is needed to translate these findings into clinical treatments but the study is an important step in potentially combatting one of the most devastating forms of cancer.

The parasite, Toxoplasma gondii, causes toxoplasmosis, an infection that is usually mild but can pose serious risks to pregnant women and people with weakened immune systems. The new study, led by the University of South Florida, adapts fluorescent imaging techniques typically used in human cell research to track the parasite’s development.

A hidden threat with limited treatment options

Toxoplasma is commonly spread through undercooked meat or contaminated produce. While early-stage infections can be treated, options are limited once the parasite becomes chronic.

“Though the parasite can be repressed in the acute stage, it requires drugs that can be toxic if taken long term,” said Elena Suvorova, an associate professor at the USF Health Morsani College of Medicine. “If you can’t catch toxoplasmosis during this time, the parasite turns chronic. In this stage, it hides from the immune system and forms cysts in the brain, for which there are currently no cures.”

The lack of effective long-term treatments has driven efforts to better understand how the parasite grows and spreads within the body.

Elena Suvorova and Mrinalini Batra observing detailed Toxomplasma cells in the lab. Credit: USF.

An unusual and poorly understood cell cycle

One of the biggest challenges facing researchers has been Toxoplasma’s unconventional cell cycle. In most organisms, cells grow, duplicate their DNA and then divide into two identical cells in a predictable sequence.

“Toxoplasma doesn’t follow this standard pattern,” said co-author Mrinalini Batra, a research scientist involved in the study. “Scientists knew it had to go through similar stages because it reproduces but they didn’t know how those stages were arranged or whether they even existed in the same way as they do in human cells. That made it hard to understand how this parasite grows and spreads.”

Without a clear picture of this process, identifying ways to stop the parasite from multiplying has proved difficult.

Fluorescent breakthrough reveals growth stages

To overcome this, the research team adapted a fluorescent imaging system to track proteins linked to specific stages of the parasite’s growth. After extensive testing, they identified a protein known as PCNA1, located in the parasite’s nucleus, which changes behaviour as the organism progresses through its cycle.

“When we attached two copies of a bright neon green tag to this protein, the signal became strong and clear,” Batra said. “This allowed us to determine the parasite’s stage simply by watching how the glowing protein behaved in the cell cycle. For the first time, researchers were able to clearly map Toxoplasma’s cell cycle.”

The findings demonstrated that while the early stages of growth follow a more conventional pattern, later stages overlap rather than occurring one after another.

“These latter stages are similar to a fork’s structure,” Suvorova said. “Toxoplasma’s cell cycle begins with one straight handle and then several prongs that branch off, allowing as many as three cell cycle phases to occur simultaneously. This unusual pattern helps the parasite multiply rapidly and evade the host’s immune system before forming cysts in the brain.”

Pathway to new treatments

By mapping the parasite’s life cycle in detail, researchers now hope to identify vulnerabilities that could be targeted by new therapies. The team is already investigating how different drugs affect specific stages of the cycle, with the aim of developing safer and more effective treatments.

Huntington’s disease gradually robs people of movement, memory and personality. It is caused by a toxic form of the huntingtin protein, which accumulates in brain cells and eventually destroys them. Although researchers have long known that this protein can spread from cell to cell, the exact mechanism behind this process was not clear.

Now, scientists from Florida Atlantic University and international collaborators have identified a previously unknown pathway that enables neurons to pass harmful material to neighbouring cells through tiny tube-like connections. The findings show that blocking this pathway can significantly reduce the spread of the disease-causing protein.

Tiny cellular ‘bridges’ enable toxic spread

The study focuses on microscopic structures known as tunnelling nanotubes, which act as direct bridges between cells. Unlike chemical signals that travel through surrounding space, these nanotubes allow cells to transfer proteins and other materials directly.

While such connections can help healthy cells respond to stress or injury, they can also be hijacked to spread harmful proteins.

Researchers discovered that a protein called Rhes works alongside a bicarbonate transporter typically involved in regulating cellular acidity, called SLC4A7. Together, these proteins promote the formation of nanotubes, effectively creating pathways for the toxic huntingtin protein to move between neurons.

Tunnelling nanotubes connect Rhes expressing striatal neuronal cells. Credit: Emaad Mirza, Florida Atlantic University.

Key protein partnership identified

“This work fundamentally changes how we think about disease progression in Huntington’s,” said Dr Srinivasa Subramaniam, Associate Professor in the Department of Chemistry and Biochemistry at Florida Atlantic University and a senior author of the study. “We’ve known that neurons somehow pass toxic proteins to one another but now we can see the machinery that makes that possible. By identifying SLC4A7 as a key partner of Rhes, we’ve uncovered a new and potentially druggable target to stop that spread at its source.”

Using advanced protein-mapping techniques, the team found that Rhes binds directly to SLC4A7 at the cell membrane. This interaction triggers changes that encourage nanotube growth. When SLC4A7 was blocked, either genetically or with drugs, nanotube formation was prevented and the spread of the toxic protein was largely halted.

Promising results in animal studies

The findings were not limited to laboratory cell models. In mice engineered to develop Huntington’s disease, those lacking SLC4A7 showed a marked reduction in the transfer of toxic protein between neurons in the striatum, the brain region most affected by the condition.

This suggests that targeting the newly identified pathway could slow disease progression by containing damage before it spreads further.

Wider implications for other diseases

The discovery could have implications beyond Huntington’s disease. Tunnelling nanotubes have also been linked to other neurodegenerative conditions, including those involving tau protein, as well as cancer, where similar structures help tumour cells share resources and resist treatment.

“This research shines a spotlight on an entirely new way cells communicate in health and disease,” said Dr Randy Blakely, Executive Director of the Florida Atlantic University Stiles-Nicholson Brain Institute. “By learning how harmful proteins physically move from cell to cell, we gain powerful new leverage points for therapy. The idea that we could slow or even halt disease progression by blocking these microscopic tunnels opens an exciting frontier for treating not only Huntington’s disease but a wide range of neurological disorders and cancers in the future.”

Hope for future treatments

Huntington’s disease affects an estimated three to seven people per 100,000 worldwide. Symptoms usually appear between the ages of 30 and 50 and progressively worsen, leading to severe physical, cognitive and psychiatric difficulties. There is currently no cure and treatments are limited to managing symptoms.

As scientists continue to explore how cells communicate and how these processes can go wrong, the discovery offers fresh hope that stopping diseases like Huntington’s could one day be achieved by interrupting the pathways that allow them to spread.

Current medications for schizophrenia are effective at managing hallucinations and delusions but have little impact on cognitive difficulties such as disorganised thinking and impaired decision making. These symptoms often prevent patients from working or living independently, leaving many reliant on long-term support.

Tackling the hidden burden of schizophrenia

Schizophrenia affects around 0.5 percent of the global population, including roughly two million people in the US. While antipsychotic drugs can control some symptoms, cognitive impairment is still a huge issue.

“A lot of people with schizophrenia cannot integrate well into society because of these cognitive deficits,” said corresponding author Peter Penzes, Professor of Neuroscience, Pharmacology and Psychiatry and Behavioural Sciences at Northwestern University Feinberg School of Medicine. “Our discovery could solve these challenges by establishing the basis of a revolutionary and completely novel treatment strategy through a tandem biomarker-peptide therapeutic approach.”

Discovery of a new biomarker

By analysing cerebrospinal fluid from more than 100 people with schizophrenia and healthy controls, researchers identified a circulating form of a brain protein known as Cacna2d1.

The study found that levels of this protein were significantly reduced in patients with schizophrenia. This deficiency appears to lead to overactive brain circuits, which may contribute to the disorder’s cognitive symptoms.

Synthetic protein shows promising results

To test a potential treatment, the team developed a synthetic version of the protein, called SEAD1, and evaluated it in a mouse model of genetic schizophrenia.

A single injection of SEAD1 corrected abnormal brain activity and improved behaviour linked to the disorder. Importantly, the researchers reported no observable negative side effects, such as sedation or reduced movement.

“Our treatment reopens a crucial window to rewire connections in adult brains,” said first author Marc Dos Santos, Research Assistant Professor of Neuroscience at Feinberg. “The lack of brain plasticity is believed to be a key factor in the development of symptoms in schizophrenia. Reforming synapses could also be beneficial for other mental disorders, such as depression.”

Towards more precise treatments

The researchers say the discovery could transform how schizophrenia is treated by pairing a diagnostic biomarker with a targeted therapy.

Unlike conditions such as diabetes or heart disease, psychiatric disorders lack clear biological markers, making diagnosis and treatment more difficult. The identification of Cacna2d1 as a biomarker could help pinpoint patients most likely to benefit from the new therapy.

“The clinical trials would have much higher success rate, and the treatments would work much better because you would give the new drug to the exact people who actually could respond to that drug,” said Penzes. “The next step for us would be to develop a blood biomarker to identify a subset of schizophrenia patients who can respond to this treatment and then we can give them this peptide – almost like Ozempic for schizophrenia, an injection that you can give once a week.”

Next steps and future potential

Researchers are now working to refine the synthetic protein and assess how long its therapeutic effects last. Future studies will also explore its use in people with 16p11.2 duplication syndrome, a genetic condition linked to a significantly increased risk of schizophrenia.

If successful in clinical trials, the approach could help in treating not only schizophrenia but potentially other psychiatric disorders linked to impaired brain plasticity.

The researchers from the University of California, Davis School of Medicine found that an imbalance in gut bacteria can drive the production of toxic compounds that worsen kidney damage and highlighted a potential drug that could break this cycle.

How gut imbalance worsens kidney disease

The research team discovered that impaired kidney function increases nitrate levels in the colon. These nitrates stimulate Escherichia coli (E. coli), to produce higher levels of indole. This compound is then converted into indoxyl sulphate, a toxic waste product that further damages the kidneys.

This creates a self-perpetuating feedback loop, where kidney damage fuels gut changes that then accelerate further decline.

“Previous research has shown that chronic kidney disease is linked to an elevated faecal abundance of Enterobacteriaceae,” said Jee-Yon Lee, first author of the study and a project scientist in the Department of Medical Microbiology and Immunology. “This study identifies nitrate from the host as a switch that turns common gut bacteria like E. coli into indole producers capable of accelerating chronic kidney disease.”

A biological diagram illustrating how chronic kidney disease turbocharges E. coli in the gut to produce indole, which is converted to indoxyl sulphate (a kidney toxin) in the liver, further worsening kidney disease. Credit: UC Regents.

A widespread health challenge

Chronic kidney disease is a progressive condition affecting around one in seven adults in the United States, or an estimated 35.5 million people. It is particularly common among those with diabetes and high blood pressure. Globally, around 788 million people were estimated to be living with the condition in 2023.

Although treatments such as haemodialysis can remove many toxins from the blood, indoxyl sulphate is difficult to eliminate because it binds tightly to proteins. Higher levels of this compound are associated with more severe disease.

Targeting a key enzyme

The study identified a potential way to interrupt this damaging cycle by blocking a single enzyme in the gut known as inducible nitric oxide synthase (iNOS).

“By identifying the driver responsible for an increase of Enterobacteriaceae during chronic kidney disease and by demonstrating the importance of these bacteria for indole production and disease progression, our research points to iNOS as a potential target for intervention strategies,” said Andreas Bäumler, senior author of the study.

Experiments in mice showed that kidney dysfunction increased activity of the gene responsible for producing iNOS. This led to higher nitric oxide levels which then formed nitrate and fuelled bacterial growth and toxin production.

Promising early results

To test a possible treatment, researchers used aminoguanidine, an investigational drug that inhibits iNOS. Mice given the drug showed lower nitrate levels in the gut, reduced indoxyl sulphate and improved kidney health.

Human stool samples showed similar patterns to those seen in mice. However, increased indole production only occurred when nitrate was present.

Caution and next steps

Despite the promising findings, researchers say further work is needed. Clinical trials will be required to determine whether targeting iNOS is safe and effective in people with chronic kidney disease.

They also caution that the gut microbiome is highly complex, and E. coli is not the only bacterium capable of producing indole. Long-term suppression of nitrate pathways may have unintended consequences.

“This study shows that altering the gut environment – not just the microbes themselves – can have profound effects on disease progression,” Bäumler said. “Targeting host pathways that shape microbial metabolism may represent a new way to intervene in chronic kidney disease.”

The findings will be presented at the International Conference on Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders 2026 in Copenhagen.

Targeting toxic protein build-up

Parkinson’s disease, which affects more than six million people worldwide, is driven in part by the build-up of misfolded proteins known as α-synuclein. These proteins form toxic aggregates in the brain, contributing to the death of nerve cells and the progression of symptoms.

PRI-101 has been developed using Priavoid’s proprietary ‘detangler’ platform and is designed to bind to these harmful aggregates and break them apart. By converting them back into non-toxic forms, the drug aims to counteract the disease processes seen not only in Parkinson’s but also in related conditions such as multiple system atrophy and Lewy body dementia.

Promising preclinical findings

In a series of laboratory and animal studies, PRI-101 directly targeted and reduced pathological α-synuclein aggregates across multiple models of Parkinson’s disease.

In vitro experiments showed that the drug could disassemble preformed fibrils of α-synuclein and deactivate their ability to spread, with effects increasing over time and at higher concentrations. Ex vivo studies using post-mortem brain samples from patients with Parkinson’s disease, multiple system atrophy and Lewy body dementia also showed reduced levels of these aggregates.

Further pharmacokinetic testing confirmed that PRI-101 can cross the blood-brain barrier and reach the brain in meaningful concentrations, a critical requirement for neurological treatments.

In more complex models, including human brain organoids and two different mouse models of Parkinson’s disease, the therapy reduced both α-synuclein aggregates and levels of phosphorylated α-synuclein.

Notably, in vivo studies found that treatment with PRI-101 was associated with longer median survival compared with placebo. Both short-term and long-term dosing led to reductions in protein aggregation in the brain, including in the substantia nigra, which is heavily affected in Parkinson’s disease. These changes were accompanied by measurable improvements in behavioural performance.

“Parkinson’s disease affects more than 6 million people worldwide and remains an area of profound unmet medical need, with patients still lacking therapies that meaningfully alter the course of disease,” said Dr Antje Willuweit, Director Preclinical Development at Priavoid GmbH. “Taken together, these preclinical data suggest that PRI-101 has the potential to be a first-in-class therapeutic candidate with disease-modifying potential for Parkinson’s disease and other related synucleinopathies. We look forward to advancing this candidate towards the clinic to address a substantial need for new disease-modifying therapeutic options.”

Next steps towards the clinic

While the findings are still at an early stage, they add to the development of treatments that go beyond symptom management and target the root causes of neurodegenerative disease.

Priavoid plans to continue advancing PRI-101 towards clinical development, with the aim of evaluating its safety and effectiveness in human patients. If successful, the approach could represent a new class of therapies designed to tackle protein aggregation.

Link between blood inflammation and tumour behaviour

Immunotherapy has changed care for many bladder cancer patients, but a proportion still do not benefit from the treatment.

In an effort to change this, researchers focused on markers of inflammation in the blood, particularly C-reactive protein (CRP) and interleukin-6 (IL-6). While high levels of these markers have long been associated with poorer outcomes, their direct connection to tumour activity had not been fully understood.

The team discovered that elevated CRP and IL-6 levels are linked to a specific group of immune cells within tumours known as SPP1+ macrophages. These cells interfere with the body’s ability to fight cancer by suppressing T cells, which are critical for attacking tumour cells.

When T cells are shut down in this way, immunotherapy drugs called immune checkpoint inhibitors become, less effective.

New insights into treatment resistance

“Immune checkpoint inhibitors have changed how we treat bladder cancer but many patients do not have long-lasting responses,” said Dr Nina Bhardwaj, MD, Director of Immunotherapy and Ward-Coleman Chair in Cancer Research at the Icahn School of Medicine. “We found that common blood markers like CRP and IL-6 are not just general signs of inflammation. They reflect a specific immune process inside the tumour that may block treatment.”

To reach these conclusions scientists analysed tumour samples using advanced genetic techniques. They created the largest single-cell atlas of bladder tumours to date and combined it with RNA sequencing data from multiple patient groups treated with immunotherapy.

Their analysis showed that tumours from patients with high IL-6 levels were more likely to contain the suppressive SPP1+ macrophages. Further investigation revealed that these cells inhibit T cells partly through IL-6-related signalling pathways.

In contrast, the researchers also identified another type of macrophage marked by CXCL9, which appears to activate T cells and is associated with stronger immune responses.

Implications for future treatments

“Our study shows that systemic inflammation can provide insight into what is happening inside tumours,” said Dr Diego Chowell, Assistant Professor of Artificial Intelligence and Human Health and Immunology and Immunotherapy at the Icahn School of Medicine. “Inflammatory signals in the blood reflect specific immune programs that suppress T cells and limit the effectiveness of immunotherapy.”

By connecting inflammation in the bloodstream with immune dysfunction in tumours, the findings point to potential new treatment strategies. Future therapies could aim to block or reprogramme harmful macrophages, which would restore immune activity and improve patient outcomes.

“For clinicians, these results suggest that commonly used blood tests may provide insight into what is happening inside a patient’s tumour before treatment begins,” said Dr Matthew Galsky, MD, Director of Genitourinary Medical Oncology and Deputy Director of the Mount Sinai Tisch Cancer Center. “This framework may help identify patients who are more likely to have resistance to immunotherapy and support testing new combination treatment strategies.”

Hope for patients and ongoing research

The research also supports ongoing clinical trials investigating drugs that target IL-6 signalling and related inflammatory pathways alongside immunotherapy.

For patients, the findings offer a clearer explanation of why some bladder cancers do not respond well to treatment. The team is now continuing to study SPP1+ macrophages to better understand how they suppress the immune system and how they might be targeted in future therapies.

The poster will showcase preclinical data for LGTX-101, the company’s selectivity-enhanced Nectin-4 x CD3 T-cell engager (TCE), highlighting its potential as a targeted cancer therapy.

Targeted T-cell activation

According to the data, LGTX-101 demonstrated robust T-cell activation in primary bladder cancer co-culture models at concentrations below 5 pM. Importantly, the studies showed no evidence of T-cell activation when peripheral blood mononuclear cells (PBMCs) were cultured with human primary keratinocytes, which naturally express Nectin-4.

This selectivity suggests that LGTX-101 may effectively target tumour cells while sparing healthy tissues.

Tumour regression in preclinical models

In vivo studies using a humanised BT-474 xenograft mouse model showed robust and reproducible regression of established tumours. The researchers observed more than 90 percent tumour growth inhibition at dose levels as low as 0.1 mg/kg, demonstrating the potent antitumour activity of LGTX-101.

Additionally, preliminary pharmacokinetic data indicate that the antibody could support a clinical dosing regimen ranging from every two weeks to every four weeks, potentially offering a convenient schedule for patients in future trials.

Leveraging AI in drug discovery

LabGenius has emphasised the role of AI and machine learning in accelerating the development of next-generation antibody therapeutics. By integrating computational approaches with high-throughput experimentation, the company aims to design highly selective molecules capable of potent tumour targeting while minimising off-target effects.

The presentation at AACR 2026 will provide attendees with an opportunity to review the full dataset and explore the potential of AI-driven bispecific antibody design in advancing targeted cancer therapies.

The poster titled ‘A Novel Machine-Learning Derived Nectin-4 x CD3 Bispecific T-Cell Engager, LGTX-101, Demonstrates High Degrees of Tumour Selectivity and Potently Induces Tumour Regression in vivo’, will be presented on Monday 20th April 2026, from 09:00 to 12:00 PDT. It will be displayed in Section 10, Board 18 at the San Diego Convention Center.

Harnessing bacteria to fight tumours

Despite advances in cancer treatment, many therapies are limited by the complexity of the disease and the difficulty of targeting tumours without harming healthy tissue.

In this study, scientists investigated whether bacteria could be used as a delivery system for anti-cancer drugs. Bacteria naturally interact with the human body and can thrive in tumour environments, making them a potentially useful tool for targeted therapy.

The team engineered EcN to produce Romidepsin, an approved anti-cancer drug known for its tumour-inhibiting properties. Using advanced genetic and genomic techniques, they created a modified strain capable of synthesising the drug.

Promising results in mouse models

To test the therapy, researchers developed a mouse model using breast cancer cells that form tumours. The engineered bacteria were then introduced into the mice.

Results showed that EcN successfully colonised the tumours and released Romidepsin in both laboratory and living conditions. This demonstrated the bacteria’s ability to act as a targeted delivery system, producing and releasing the drug directly at the tumour site.

Such an approach could reduce the side effects often associated with conventional cancer treatments, which can impact healthy cells as well as cancerous ones.

Cautious optimism for future applications

Despite the promising findings, researchers stress that the therapy is still in its early stages. The treatment has not yet been tested in humans and further studies are required to assess safety, potential side effects and how the engineered bacteria might be controlled or eliminated after treatment.

There are concerns about possible adverse outcomes and the long-term impact of introducing modified bacteria into the body. These factors could influence whether the therapy becomes viable in clinical settings.

A step towards innovative cancer care

While still experimental, the research highlights the growing interest in using engineered biological systems to tackle complex diseases. If eventually proven safe and effective in humans, bacteria-based therapies could represent a significant shift in how cancer is treated, offering more precise and potentially less harmful options for patients.

The technique, known as Sonoporation-assisted Precise Intracellular Nanodelivery (SonoPIN), achieved powerful results in early laboratory experiments. Researchers reported that 50 percent of targeted cancer cells were destroyed, while 99 percent of non-targeted cells remained healthy.

The findings highlight the potential for a more precise approach to cancer treatment with minimal side effects.

Unlocking the potential of PROTACs

The research focuses on a new class of therapeutics called proteolysis-targeting chimeras (PROTACs) which are designed to break down harmful proteins inside cells. These molecules work by binding to a target protein and recruiting an enzyme that marks it for destruction by the cell’s natural waste disposal system.

In cancer therapy, PROTACs have been used to degrade a protein called BRD4, which plays a key role in tumour growth. Removing this protein disrupts the cancer cells’ ability to multiply and survive, forcing them to self-destruct.

Despite their promise, PROTACs face two major challenges: they are too large to easily enter cells and they can also affect healthy cells if delivered indiscriminately.

“PROTAC molecules are too big to get into cells in the first place,” said Yuqi Wu, a doctoral student working in the laboratory of Tony Jun Huang, the William Bevan Distinguished Professor of Mechanical Engineering and Materials Science at Duke. “But with our SonoPIN platform, the PROTACs can enter into targeted cancer cells while almost completely ignoring non-targeted cells.”

A graphical chart demonstrating how the SonoPIN platform works. Microbubbles targeted to cancer cells are burst by ultrasound waves, creating small pores in nearby cell membranes large enough for pharmaceuticals like PROTACs to enter. Credit: Duke University.

How SonoPIN works

SonoPIN uses microscopic bubbles that are usually employed in medical imaging to enhance ultrasound scans. When exposed to controlled ultrasound waves, these bubbles collapse in a way that creates tiny temporary openings in nearby cell membranes.

“This process is less like an explosion and more like a temporary, controlled mechanical opening,” said Huang. “While it involves physical force, because cell membranes are fluid and dynamic, they naturally self-heal and close these pores within minutes if not seconds.”

These fleeting openings allow large molecules such as PROTACs to pass inside the cell. To ensure precision, the researchers coated the microbubbles with synthetic nucleic acid strands that bind specifically to cancer cell receptors.

Promising early results

In testing, the team fine-tuned ultrasound settings to maximise delivery efficiency. By attaching fluorescent markers to the PROTACs they were able to track how effectively the drugs entered cells.

After just one minute of ultrasound exposure, treated cancer cells showed fluorescence levels seven times higher than those receiving conventional delivery methods. This confirmed that significantly more PROTAC molecules had entered the cells, leading to the destruction of half the cancer cells while leaving most healthy cells unharmed.

Next steps for cancer treatment

The researchers now plan to move into animal studies and have already filed a patent for the technology. They believe that injecting both PROTACs and targeted microbubbles into the bloodstream, combined with focused ultrasound, could offer a powerful and precise cancer therapy.

“Because SonoPIN relies on a mechanical delivery approach rather than biological engulfment, it could theoretically deliver therapeutics of almost any size,” said Huang. “We would also be excited to see how it performs with therapeutics such as large gene-editing complexes.”