Why Cancer Spreads: Scientists Uncover a New Clue Inside the Cell’s Power Plant

Mitochondria may be best known for fueling cells, but new research reveals they also play a surprising role in the spread of cancer.

Rockefeller researchers have discovered that the antioxidant glutathione, acting within mitochondria, plays a crucial role in allowing breast tumors to spread to the lung.

Mitochondria are best known as the cell’s powerhouse, but growing evidence indicates they also play a central role in driving cancer. New research has identified the mitochondrial metabolite glutathione as a key factor that enables breast cancer cells to detach from the primary tumor, spread through the body, and establish themselves in new tissues.

The findings are among the first to link a specific mitochondrial metabolite to metastasis, with strong implications for the study of cancer at the cellular level. “We hope that our work will bring more attention to how organelles and their metabolites are relevant to cancer biology,” says Kivanç Birsoy, head of the Laboratory of Metabolic Regulation and Genetics at Rockefeller.

A mysterious connection with metastasis

Most cancer deaths occur not because of the original tumor, but due to the disease’s spread. Because metastasis is the leading cause of cancer mortality, researchers have long sought to uncover the mechanisms that allow cancer cells to break free from their primary site and colonize distant organs.

Previous studies have shown that metabolites such as lactate, pyruvate, glutamine, and serine each contribute to different stages of metastasis. Since mitochondria not only produce cellular energy but also generate metabolites, it is not surprising that recent work has tied mitochondrial activity to the spread of breast, renal, and pancreatic cancers.

Yet the exact molecular players remained unclear. “Mitochondria have thousands of metabolites, and it’s been difficult to determine which are important to tumor formation and growth, and which initiate metastasis,” Birsoy explains.

Cells under stress

To address this question, Birsoy and his colleagues used a protein-tagging approach that allowed them to distinguish between cells that remained in the breast tumor and those that had spread to the lung. Led by graduate fellow Nicole DelGaudio and postdoctoral fellow Hsi-wen Yeh, the team then examined how the metabolite composition of mitochondria changed when cancer cells established themselves in new tissues.

“These techniques allowed us to, in an unbiased manner, see the difference between what’s essential in metastasis and what’s essential in the primary tumor,” DelGaudio says.

Out of thousands of mitochondrial metabolites, glutathione emerged as a striking candidate. This antioxidant, known for reducing oxidative stress, aiding detoxification, and supporting immune function, was found in sharply elevated levels within metastatic cancer cells that had reached the lung. To validate the observation, the researchers employed spatial metabolomics to directly visualize glutathione distribution in lung tissues.

The investigation then shifted toward mitochondrial membrane proteins. Screening revealed that one stood out as indispensable for metastatic cancer cells: SLC25A39, the transporter that imports glutathione into mitochondria. Together, the findings established a direct connection between glutathione and its transporter, showing that mitochondrial glutathione import through SLC25A39 is a critical driver of cancer metastasis.

Birsoy and colleagues also found how mitochondrial glutathione drives cancer spread: not by acting as an antioxidant—an effect ruled out through multiple experiments—but by signaling to activate ATF4, a transcription factor that helps cancer cells survive in low-oxygen conditions. This also pinpointed when glutathione is specifically required: during the early steps of metastatic colonization, when cancer cells adapt rapidly to the stressful environment of a new tissue.

A familiar culprit

This work builds on recent significant work from the Birsoy lab. In 2021, his team was the first to demonstrate that SLC25A39 is the transporter that brings glutathione into the mitochondria; in 2023, they showed that SLC25A39 is not only a transporter but a dynamic sensor that regulates the amount of glutathione in the mitochondria and adjusts those levels accordingly. So when this metabolite and its mitochondrial transporter showed up in cancer screenings, Birsoy knew where to take his experiments next.

“Because we found this transporter earlier and knew how to block the entry of glutathione, we already had the tools necessary to investigate its role in cancer metastasis,” he says.

The findings may have clinical implications—especially since the team also found that breast cancer samples from patients whose disease had spread to the lung showed elevated SLC25A39, and that higher SLC25A39 expression was strongly correlated with poorer overall survival in breast cancer patients. One day, a small molecule that targets this metabolite by blocking its transporter could potentially forestall breast cancer metastasis, with fewer side effects than sweeping therapies that target more general cellular processes.

In the short term, however, the paper emphasizes the importance of nailing down just how metabolites within different compartments operate within our cells.

“We’re trying to make our knowledge of metabolism more precise,” Birsoy says. “It’s not just about some metabolite levels going up and others going down. We need to look at the organelles, the precise compartments, to understand how metabolites influence human health.”

https://scitechdaily.com/why-cancer-spreads-scientists-uncover-a-new-clue-inside-the-cells-power-plant/

Surgery to treat chronic sinus disease more effective than antibiotics: Study

A comprehensive clinical trial sponsored by University College London (UCL), the University of East Anglia, and Guy's and St Thomas' NHS Foundation Trust found that sinus surgery is more effective than antibiotics at treating chronic rhinosinusitis.

One in every ten people in the United Kingdom suffers from chronic rhinosinusitis (CRS), sometimes known as sinusitis. Symptoms include a blocked and runny nose, loss of smell, facial pain, fatigue, and worsening of respiratory difficulties, such as asthma. It generally resembles the symptoms of a bad cold, but it can persist for months or even years.

The team conducted a randomised controlled patient trial comparing sinus surgery with long-term antibiotic use and a placebo.

More than 500 patients from around the UK participated, all of whom used nasal steroids and saline rinses as part of their usual care - both of which have been shown to help alleviate the condition.

The researchers found that surgery was effective at relieving sinusitis symptoms, and trial participants who underwent surgery were still feeling better six months later, according to the findings published in The Lancet. Of those who underwent surgery, 87 per cent said their quality of life had improved six months on.

A three-month course of low-dose antibiotics was not found to be helpful, as there was no significant difference in outcomes between those on antibiotics and those in the placebo arm of the trial.

The study is part of the MACRO programme, involving a collaborative group of researchers from UCL (the trial's sponsor), the University of East Anglia (UEA), Guy's and St Thomas' NHS Foundation Trust, the University of Southampton, the University of Oxford, UCLH, and Imperial College London. The programme is funded by the National Institute for Health and Care Research.

Lead author Professor Carl Philpott, from UEA's Norwich Medical School, one of the Chief Investigators of the MACRO trial, said, "Chronic rhinosinusitis causes the spaces inside the nose and head, called sinuses, to become inflamed and swollen. This common condition keeps mucus from draining. It gives patients a very stuffy nose, breathing through the nose can be really hard, and it is the major underlying cause of smell loss in the general population. What we found is that surgery was effective at reducing symptoms six months on, while taking the course of antibiotics seemed to make little difference."

"We hope our findings will help reduce the length of time for patients to get treatment. Streamlining clinical pathways will help reduce unnecessary visits and consultations, and save on healthcare resources."

For the trial, all participants received nasal steroids and saline rinses as standard care, alongside their randomly allocated treatment option of either sinus surgery, antibiotics or placebo tablets. They were followed up after three and six months, where researchers examined their nose and sinuses, took airflow readings and conducted smell tests, to gauge the success of each treatment in terms of improvement of symptoms, quality of life and possible side effects.

Professor Claire Hopkins (Guy's Hospital, London), one of the Chief Investigators of the MACRO trial, said, "Although sinus surgery is commonly performed within the NHS, uncertainty regarding its effectiveness has led to restricted access for many patients in the NHS. The results of the MACRO trial highlight the significant improvements in quality of life that many patients experience after surgery, and should give them and their referring primary care doctors more confidence in seeking treatment for chronic rhinosinusitis. We hope that this work will enhance the care for adult patients with chronic rhinosinusitis within the NHS, and beyond."

Study co-author Professor Anne Schilder (UCL Ear Institute), director of the NIHR UCLH Biomedical Research Centre Hearing Health Theme, who is leading the project at UCL, commented, "Here we have provided robust evidence that surgery is an effective means to treat chronic rhinosinusitis when local treatments have failed, which should be welcome news to the large numbers of people with the condition."

"The MACRO trial has shown the value of research collaboration across specialities and organisations. It was the first NIHR programme grant for our speciality, recognising the need for better evidence for the management of common ENT conditions and the strength of our collaborative team. The commitment of our investigators, research nurses and of course our patient participants across 20 UK sites made it a success."

Jim Boardman, MACRO patient representative, said, "I've lived under a cloud for years with CRS, as have many others I've met with the same condition. There's a persistent headache and blocked nose along with the loss of sense of smell, which removes a whole dimension of everyday experience and enjoyment. A clear path to successful treatment will be welcomed by all CRS sufferers."

The researchers are now continuing their research to assess the cost-effectiveness of sinus surgery, while also continuing to follow up trial participants over longer periods of time to see how long the benefits last. (ANI)

https://www.tribuneindia.com/news/health/surgery-to-treat-chronic-sinus-disease-more-effective-than-antibiotics-study/

Common heart attack drug may raise death risk in some women: Study

Key Points

1 Beta blockers show no benefit for uncomplicated heart attack patients

2 Women face 2.7% higher mortality risk with beta blockers

3 Men did not experience increased risk from the treatment

4 Study followed 8,505 patients across 109 hospitals for nearly four years

Beta blockers, the standard treatment after a heart attack for the last 40 years, may offer no benefit for heart attack patients and can raise death risk in some women, according to a study on Saturday that called for a rejig into the standard treatment paradigm.

Beta blockers are drugs commonly prescribed for a range of cardiac conditions, including heart attacks. It provides no clinical benefit for patients who have had an uncomplicated myocardial infarction with preserved heart function.

The study presented at the European Society of Cardiology Congress in Madrid and simultaneously published in The New England Journal of Medicine and in the European Heart Journal, showed that women treated with beta blockers had a higher risk of death, heart attack, or hospitalisation for heart failure compared to women not receiving the drug.

However, men did not have this increased risk.

“The study will reshape all international clinical guidelines,” said senior investigator Valentin Fuster, President of Mount Sinai Fuster Heart Hospital.

“Currently, more than 80 per cent of patients with uncomplicated myocardial infarction are discharged on beta blockers. The findings represent one of the most significant advances in heart attack treatment in decades,” said principal investigator Borja Ibáñez, Scientific Director at Centro Nacional de Investigaciones Cardiovasculares (CNIC) in Spain.

Although generally considered safe, beta blockers can cause side effects such as fatigue, bradycardia (low heart rate), and sexual dysfunction.

The international study enrolled 8,505 patients across 109 hospitals in Spain and Italy. Participants were randomly assigned to receive or not receive beta blockers after hospital discharge. All patients otherwise received the current standard of care and were followed for a median of nearly four years.

The results showed no significant differences between the two groups in rates of death, recurrent heart attack, or hospitalisation for heart failure.

A subgroup analysis found that women treated with beta blockers experienced more adverse events. Results show women treated with beta-blockers had a 2.7 per cent higher absolute risk of mortality compared to those not treated with beta-blockers during the 3.7 years of follow-up of the study.

Beta Blockers Raise Death Risk in Women After Heart Attack Study

A major international study has found that beta blockers may actually harm some women after heart attacks. The research showed women treated with these drugs had a 2.7% higher risk of death compared to those not receiving them. Surprisingly, the study found no clinical benefit for any patients with uncomplicated heart attacks. These findings could completely change how doctors treat heart attack patients worldwide.

https://www.newkerala.com/news/o/common-heart-attack-drug-raise-death-risk-women-study-917

Train ASHA workers to identify babies with Spinal Muscular Atrophy: Experts

Key Points

1 Train ASHA workers to recognize early SMA developmental signs

2 SMA affects 1 in 7,500 Indian babies with motor function challenges

3 Early screening crucial for managing rare genetic disorder

4 Lack of national registry hampers comprehensive disease understanding

Training ASHA workers to identify red flags in babies with Spinal Muscular Atrophy can be a major boost in the fight against the rare disease in India, said health experts on Saturday.

SMA is a rare genetic disorder that affects the motor capabilities of the person affected.

In SMA, intellectual capacities remain normal, but motor capacities are affected.

Speaking to IANS, Dr. Rahul UR, State Nodal Officer - Child Health and Rare Diseases, National Health Mission, Kerala, said that understanding the disease process is crucial.

"SMA is a genetic disorder that presents in early childhood and is often mistaken for a simple developmental delay, unlike adult motor issues that might lead to needing a wheelchair," Rahul said.

SMA is categorised into four types -- numbered as type 0, 1, 2, 3, and 4.

Type 0 are those babies who don't survive the labour process due to a lack of muscle function, resulting in death. In Types 1 to 4, the recruitment of the motor units is affected, resulting in a neuromuscular disorder.

The expert cited that a key problem is that many parents are unaware of the major developmental milestones a child should achieve by a certain age.

Therefore, building awareness starts with understanding the normal stages of a child's development. This education can easily be integrated into existing national health programmes.

"Missing key milestones, such as attaining neck control or learning to stand by the appropriate age, are critical indicators that require further evaluation," Rahul said.

For example, a child with Type 1 SMA will never achieve neck control without treatment. Unfortunately, some families might believe their child will simply catch up later.

"This causes them to wait, delaying both evaluation and diagnosis. For a child with Type 1 SMA, such a delay can be fatal within the first year of life," Rahul told IANS.

To avoid this, "community health professionals, like ASHA workers, can be trained to identify red flags. This must be complemented by a push for early screening and newborn testing programmes to catch these conditions systematically," the expert said.

Importantly, the expert cited the lack of standard guidelines or protocols for the management of SMA as well as the lack of a national registry to understand the number of SMA patients. There is also a lack of sustainable funding, which can help improve diagnostics and treatments for the disease.

"As per literature, the estimated number of SMA cases in India is around 1 in 7,500. However, we do not have an exact registry or records of this condition. This issue is not limited to the case of Spinal Muscular Atrophy but most rare diseases in India," the doctor said.

"Today, the SMA ecosystem in India faces critical gaps -- delayed diagnosis and initiation of treatment due to limited awareness and inadequate access to genetic testing facilities, limited number of Centres of Excellence with trained specialists and multidisciplinary teams to provide holistic care and lack of sustainable funding to access treatment," Professor Sheffali Gulati, neurologist at the Department of Paediatrics, AIIMS, New Delhi, told IANS.

The continued delay in building robust data systems threatens public health significantly because the healthcare workers cannot plan for sustainable, population-level support without it.

Gulati noted that although innovative therapies are now available and have shown proven outcomes in preserving motor function and improving quality of life, access remains a major challenge.

"To truly change the trajectory for patients, India urgently needs a sustainable funding mechanism that ensures equitable access to these life-changing therapies," she added.

To bridge these gaps, the experts urged governments, NGOs, patient bodies, the medical fraternity, and the industry to come together with a shared commitment.

ASHA Workers Key to Early SMA Detection in India

Spinal Muscular Atrophy (SMA) is a rare genetic disorder affecting motor capabilities in children with significant diagnostic challenges. Health experts are advocating for community health workers like ASHA to be trained in early detection and milestone recognition. The lack of a national registry and standardized screening protocols currently hinders comprehensive management of the condition. Collaborative efforts between governments, medical professionals, and patient bodies are essential to improve diagnosis and treatment accessibility.

https://www.newkerala.com/news/o/train-asha-workers-identify-babies-spinal-muscular-atrophy-experts-626

Lung cancer most prevalent worldwide, experts warn of high mortality rates

Experts during the lung cancer awareness talk at Livasa Hospital.

Lung cancer has emerged as the most prevalent cancer globally, raising significant concerns among health experts.

According to the latest global data, nearly 2.4 million new cases were diagnosed in 2022, making it the leading cancer in terms of both incidence and mortality. Countries such as China, the United States, Japan and India are among the top four nations with the highest number of cases.

Alarmingly, India is also listed as one of the countries with the highest number of lung cancer-related deaths.

Highlighting the severity of the issue, Dr Sonal, Consultant in Pulmonary Medicine at Livasa Hospital, stated, “One in five cancer-related deaths is attributed to lung cancer. It is one of the deadliest cancers, with smoking being the primary cause, responsible for nearly 80 per cent of all cases.” Dr Sonal explained that lung cancer typically originates in the lungs, often in the cells lining the air passages, and can spread aggressively if not detected in its early stages.

Addressing the signs and symptoms, Dr Kritarth, Consultant in Pulmonary Medicine, explained that lung cancer often presents as a persistent cough, chest pain, difficulty breathing, or coughing up blood. However, the real challenge, according to him, is that the disease often remains silent in its early stages. “By the time symptoms appear, the cancer has usually advanced, significantly reducing the chances of successful treatment,” he added.

Both experts stressed the importance of early detection through regular screenings. Dr Kritarth emphasised that detecting lung cancer in its early stages and initiating timely treatment can notably improve the five-year survival rate. “Screening is a vital preventive step and plays a crucial role in saving lives,” he asserted.

Dr Sonal also highlighted the challenge of limited access to lung cancer screening in many parts of the world, including India. “This lack of availability is a major barrier in the fight against lung cancer. Governments and health institutions must collaborate to make screening and early diagnostic facilities more accessible,” she urged.

Experts also noted that, besides smoking, air pollution, exposure to toxic chemicals, and genetic factors contribute to the rising incidence of lung cancer. With increasing urbanisation and pollution, risk factors are escalating, making it even more urgent to raise awareness about prevention.

https://www.tribuneindia.com/news/jalandhar/lung-cancer-most-prevalent-worldwide-experts-warn-of-high-mortality-rates/

Revised AHA guidelines on hypertension: What's new?

New AHA hypertension guidelines suggest diet is key to control.

• Hypertension, or high blood pressure, affects around one in every three adults worldwide.
• It is a risk factor for several health conditions, including heart attack, stroke, heart failure and kidney damage.
• The American Ηeart Association has recently updated its 2017 guidelines on the prevention and management of hypertension, including new research information for the 2025 guidelines.
• It advises that anyone can develop high blood pressure but that diet and lifestyle modifications can prevent or control the condition for many people.

The American Heart Association (AHA)Trusted Source has recently published revised its guidelines on hypertension. They state that the condition is the leading risk factor for stroke and a number of heart diseases, such as coronary artery disease, heart failure, and atrial fibrillation (AFib).

The World Health Organization (WHO)Trusted Source states that one in three adults, or 1.3 billion people, around the world have hypertension, so preventing, detecting and treating it could prevent 76 million deaths worldwide between now and 2050.

Blood pressureTrusted Source is recorded as systolic, referring to the maximum pressure when the heart contracts, over diastolic — the minimum pressure just before the next contraction. Ideally, it should be 120/80 millimeters of mercury (mmHg) or below.

The full guidelines, published in the journal HypertensionTrusted Source, aim to help medical practitioners detect and treat hypertension, but also contain valuable advice to help people control and manage their own blood pressure.

Cheng-Han Chen, MD, board certified interventional cardiologist and medical director of the Structural Heart Program at MemorialCare Saddleback Medical Center in Laguna Hills, CA, who was not involved in developing the guidelines, told Medical News Today that:

“The new blood pressure guidelines have several changes that emphasize earlier assessment and intervention of elevated blood pressure. In particular, it affirms the importance of lifestyle changes to help control blood pressure, such as with limiting sodium and alcohol intake, eating a heart healthy diet, maintaining physical activity, and managing weight and stress. This is a welcome message that will hopefully help us manage hypertension before it contributes to more serious cardiovascular disease.”

‘Adults should have blood pressure measured at least once a year’

To update their guidelines, the AHA carried out a comprehensive review of clinical studies, reviews and other evidence about hypertension published since February 2015.

They describe the guidelines as a “living, working document updating current knowledge in the field of high blood pressure aimed at all practicing primary care and specialty clinicians who manage patients with hypertension.”

Daniel W. JonesTrusted Source, MD, FAHA, volunteer chair of the guideline writing committee and a past-president of the AHA (2007-2008), dean and professor emeritus of the University of Mississippi School of Medicine in Jackson, MS, and a member of the writing committee for the 2017 high blood pressure guideline, told MNT that:

“All adults should have their blood pressure measured at least once a year, more often for patients with any level of high blood pressure. Patients with high blood pressure who have a reading above 180/120 mmHg should seek advice from their clinician, urgently if there are symptoms of chest pain, shortness of breath, paralysis or speech difficulty.”

New AHA hypertension guidelines: 5 key points

As part of the update, the AHA has also published a summary for patientsTrusted Source of the top 10 things that people should know about high blood pressure.

Jones highlighted the key updates for 2025, which include:

1.     the goal of achieving a systolic blood pressure of 130 mmHg or below, and ideally of 120 mmHg, for adults with high blood pressure

2.     more clear and robust evidence that intensive lowering of blood pressure reduces the risk of cognitive decline and dementia

3.     “in adults with an average blood pressure of 130/80 mm Hg [or more], and at lower 10-year cardiovascular dis­ease risk defined by the PREVENT risk calculatorTrusted Source of <7.5%, initiation of medication therapy to lower blood pressure in addition to lifestyle modification are recommended if average blood pressure remains 130/80 mmHg [or more] after an initial 3- to 6-month trial of lifestyle modification only”

4.     recommendations of “moving toward an ideal limit of 1500 mg/day [milligrams per day]” for sodium consumption

5.     the advice to stop consuming, “or at least to reduce alcohol intake to [less than] 1 drink/day for women and [less than] 2 drinks/day for men to prevent or treat elevated blood pressure and hypertension.”

To this he added that “patients with high blood pressure who have a reading above 180/120 mmHg should seek advice from their clinician, urgently if there are symptoms of chest pain, shortness of breath, paralysis or speech difficulty,” Jones advised.

How to keep your blood pressure at a healthy level

The AHA advises that anyone can develop high blood pressure, so it is important to have it checked regularly. It also states that although lifestyle and dietary changes can be effective in reducing blood pressure, many people will also need medications to get their blood pressure down to healthy levels.

“These new guidelines will hopefully encourage clinicians to further recommend lifestyle changes to patients with elevated blood pressure. They also promote the use of a specific risk calculator to help us determine which patients may benefit most from medical therapy for hypertension,” Chen told MNT.

“Some lifestyle recommendations for people trying to reduce blood pressure on their own include eating a heart healthy diet low in sodium, avoiding/eliminating alcohol intake, maintaining a healthy weight, getting regular physical activity, and managing their stress levels,” he added.

The guidelines also emphasize that losing at least 5% of your body weight if you have overweight or obesity can help lower or prevent hypertension, and advise that people can learn more about how to improve their heart and brain health from Life’s Essential 8Trusted Source, which is also published by the AHA.

https://www.medicalnewstoday.com/articles/revised-aha-guidelines-on-hypertension-whats-new

Could This Tiny Molecule Be Better Than Ozempic and Wegovy for Obesity?

Scientists have uncovered a hidden molecule in DNA that helps control fat storage, offering hope for a new kind of obesity treatment.

More than a billion people worldwide struggle with obesity, and popular treatments like Ozempic and Wegovy don’t work for everyone — and can cause unpleasant side effects.

Now, researchers have discovered a tiny, hidden molecule in our DNA that could help change that. Using cutting-edge genetic tools, they found this microprotein plays a role in how our bodies store fat, opening the door to a whole new type of weight loss treatment.

Global Obesity Crisis and Limited Treatments

Over the past three decades, obesity rates have more than doubled, now affecting more than one billion people worldwide. This widespread condition is closely tied to serious health problems, including type 2 diabetes, heart disease, chronic kidney disease, and various cancers. While existing treatments such as lifestyle changes, bariatric surgery, and GLP-1 drugs like Ozempic or Wegovy can be effective, many people face challenges in starting, completing, or sustaining these approaches, often regaining lost weight over time.

Researchers at the Salk Institute are exploring a promising new path involving microproteins. These small, often-overlooked molecules are found throughout the body and influence both health and disease. In a recent study, the team used CRISPR gene editing to analyze thousands of fat cell genes. They identified dozens of genes that appear to code for microproteins, and confirmed one that directly affects fat cell growth or the build-up of lipids (fat molecules) inside the cells.

CRISPR Unlocks New Therapeutic Possibilities

Published in the Proceedings of the National Academy of Sciences (PNAS) on August 7, 2025, the study highlights microproteins that could one day become targets for new obesity and metabolic disorder treatments. It also demonstrates how valuable CRISPR screening can be for uncovering microproteins with medical potential.

“CRISPR screening is extremely effective at finding important factors in obesity and metabolism that could become therapeutic targets,” says senior author Alan Saghatelian, a professor and holder of the Dr. Frederik Paulsen Chair at Salk. “These new screening technologies are allowing us to reveal a whole new level of biological regulation driven by microproteins. The more we screen, the more disease-associated microproteins we find, and the more potential targets we have for future drug development.”

How Fat Cells Store and Harm the Body

When people take in more energy than they burn, fat cells can increase in both size and number. These cells store extra energy as fatty molecules called lipids. While the body can tolerate some extra storage, excessive fat can build up in different areas, triggering widespread inflammation and damaging organs.

Many biological factors control this intricate energy storage system. The challenge for scientists is figuring out how to identify all of them, and more importantly, how to pinpoint which ones could lead to safe and effective treatments.

Past Drug Targets and Their Limitations

This has been a longstanding question for Salk scientists. In fact, Salk Professor Ronald Evans has been working on it for decades. Evans is an expert on PPAR gamma, a key regulator of fat cell development and a potent target for treating diabetes. Several drugs have been developed to target PPAR gamma to treat obesity, but they resulted in side effects like weight gain and bone loss. An ideal PPAR gamma-based obesity therapeutic has yet to hit the market.

When PPAR gamma drugs fell short, GLP-1 drugs entered the scene. GLP-1 is a peptide small enough to be considered a microprotein, and it serves as a blood sugar and appetite regulator. But, like PPAR gamma, GLP-1 drugs have their own shortcomings, such as muscle loss and nausea. Nonetheless, the popularity of GLP-1 drugs demonstrates a promising future for microprotein drugs in the obesity therapeutic space.

Searching the Genome’s “Dark” Regions

Saghatelian’s team is now searching for the next microprotein therapeutic with new genetic tools that bring microproteins out of the “dark.” For many years, long stretches of the genome have been considered “junk” and thus left unexplored. But recent technological advances have allowed scientists to look at these dark sections and find a hidden world of microproteins—in turn, expanding protein libraries by 10 to 30 percent.

In particular, the Salk team is using innovative CRISPR screening to scour the “dark” for possible microproteins. This approach is enabling the simultaneous discovery of thousands of potential microproteins involved in lipid storage and fat cell biology, accelerating the search for the next PPAR gamma or GLP-1 drug.

Precision Discovery Through CRISPR Screening

CRISPR screens work by cutting out genes of interest in cells and observing whether the cell thrives or dies without them. From these results, scientists can determine the importance and function of specific genes. In this case, the Salk team was interested in genes that may code for microproteins involved in fat cell differentiation or proliferation.

“We wanted to know if there was anything we had been missing in all these years of research into the body’s metabolic processes,” says first author Victor Pai, a postdoctoral researcher in Saghatelian’s lab. “And CRISPR allows us to pick out interesting and functional genes that specifically impact lipid accumulation and fat cell development.”

This latest research follows up on a prior study from Saghatelian’s lab. The previous study identified thousands of potential microproteins by analyzing microprotein-coding RNA strands derived from mouse fat tissues. These microprotein-coding RNA strands were filed away to await investigation into their functions.

The new study first expanded this collection to include additional microproteins identified from a pre-fat cell model. Notably, this new model captures the differentiation process from pre-fat cell to a fully mature fat cell. Next, the researchers screened the cell model with CRISPR to determine how many of these potential microproteins were involved in fat cell differentiation or proliferation.

“We’re not the first to screen for microproteins with CRISPR,” adds Pai, “but we’re the first to look for microproteins involved in fat cell proliferation. This is a huge step for metabolism and obesity research.”

From Mouse Models to Microprotein Shortlist

Using their mouse model and CRISPR screening approach, the team identified microproteins that may be involved in fat cell biology. They then narrowed the pool even further with another experiment to create a shortlist of 38 potential microproteins involved in lipid droplet formation—which indicates increasing fat storage—during fat.

At this point, the shortlisted microproteins were all still “potential” microproteins. This is because the genetic screening finds genes that may code for microproteins, rather than finding the microproteins themselves. While this approach is a helpful workaround to finding microproteins that are otherwise so small they elude capture, it also means that the screened microproteins require further testing to confirm whether they are functional.

And that’s what the Salk team did next. They picked several of the shortlisted microproteins to test and were able to verify one. Pai hypothesizes this new microprotein, called Adipocyte-smORF-1183, influences lipid droplet formation in fat cells (also known as adipocytes).

Adipocyte-smORF-1183: A Verified Target

Verification of Adipocyte-smORF-1183 is an exciting step toward identifying more microproteins involved in lipid accumulation and fat cell regulation in obesity. It also verifies that CRISPR is an effective tool for finding microproteins involved in fat cell biology, obesity, and metabolism.

“That’s the goal of research, right?” says Saghatelian. “You keep going. It’s a constant process of improvement as we establish better technology and better workflows to enhance discovery and, eventually, therapeutic outcomes down the line.”

Next Steps: Human Trials and Expanded Screening

Next, the researchers will repeat the study with human fat cells. They also hope their success inspires others to use CRISPR screenings to continue bringing microproteins out from the dark—like Adipocyte-smORF-1183, which until now, was considered an unimportant bit of “junk” DNA.

Further validation or screening of new cell libraries will expand the list of potential drug candidates, setting the stage for the new-and-improved obesity and metabolic disorder therapeutics of the future.

https://scitechdaily.com/could-this-tiny-molecule-be-better-than-ozempic-and-wegovy-for-obesity/