The hormone, known as FGF21 (fibroblast growth factor 21), has already attracted attention as a potential target for new therapies. Drugs designed to act on this pathway are currently being tested in clinical trials for MASH (metabolic dysfunction-associated steatohepatitis), a serious form of fatty liver disease.

Lead researcher Matthew Potthoff, Ph.D., and his team focused on understanding exactly how FGF21 produces its effects. Their results show that the hormone acts through the hindbrain, which is located in the lower back part of the brain.

Unexpected Brain Region Revealed

“In our previous studies, we found that FGF21 signals to the brain instead of the liver, but we didn’t know where in the brain,” said Potthoff, a professor of biochemistry and physiology in the OU College of Medicine and deputy director of OU Health Harold Hamm Diabetes Center. “We thought we would find that it signaled to the hypothalamus (which is widely implicated in body weight regulation), so we were very surprised to discover that the signal was to the hindbrain, which is where the GLP-1 analogs are believed to act.”

More specifically, FGF21 interacts with two parts of the hindbrain called the nucleus of the solitary tract (NTS) and the area postrema (AP). These regions then communicate with another brain structure known as the parabrachial nucleus. This chain of signaling is essential for the hormone’s ability to influence metabolism and reduce body weight.

Brain Circuit Drives Fat Burning Effects

“This brain circuit seems to be mediating the effects of FGF21,” Potthoff said. “We hope that by identifying the specific circuit, it can help in the creation of more targeted therapies that are effective without negative side effects. FGF21 analogues have side effects like gastrointestinal issues and, in some cases, bone loss.”

Although FGF21 and GLP-1 drugs affect similar areas of the brain, they work in very different ways. GLP-1 medications reduce appetite and food intake, while FGF21 increases metabolic activity, helping the body burn more energy and lose weight.

Potential for Future Obesity and Liver Disease Treatments

Potthoff and his team are optimistic that this research could lead to new treatments for both obesity and MASH.

“While this study focused on the mechanism of FGF21 to reduce body weight, additional studies are necessary to examine whether this circuit also mediates the ability of FGF21 and FGF21 analogues to reverse MASH,” he said.

CAR-based therapies have already transformed cancer treatment, particularly for blood-related cancers. While CAR-T cells are well studied, scientists are still working to understand how to optimize CAR-NK cells. One key challenge is identifying which internal signaling mechanisms allow these cells to perform at their best.

The new research addresses this gap by focusing on how specific signaling domains influence NK cell activity. By incorporating 2B4 and DAP12 into the CAR design, the researchers were able to enhance the cells’ activation state, making them more effective at targeting tumors.

Combining activation signals with drug control

The team also explored a strategy to fine-tune the cells using a temporary drug-based approach. They tested dasatinib, a drug that can briefly suppress cell activity, to see how controlled pauses might affect performance.

Their results suggest that combining optimized activation signals with reversible pharmacological control can improve both the strength and efficiency of CAR-NK therapies. This approach may help researchers design more advanced and controllable cell-based cancer treatments in the future.

Stronger tumor control in preclinical models

According to the Ribeirão Preto Blood Center Press Office, experiments in animal models showed encouraging results. CAR-NK cells engineered with 2B4-DAP12 and pretreated with dasatinib were better at controlling tumor growth compared to more traditional versions of the therapy.

Research collaboration and institutional support

The Center for Cell-Based Therapy (CTC) is one of the Research, Innovation, and Dissemination Centers (RIDCs) supported by FAPESP. It operates within the Ribeirão Preto Blood Center and is affiliated with the general and teaching hospital (“Hospital das Clínicas”) of the Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP).

Together, these findings point toward a new generation of CAR-NK therapies that could offer stronger, more adaptable ways to fight cancer.

Several factors appear to drive this decline, including accumulated cellular damage, changes in gene activity, chronic low-level inflammation, and shifts in the bone marrow environment. Even so, scientists have not fully understood how these different stresses combine to impair HSC function.

Investigating a Key Aging Pathway

To better understand this process, researchers from The University of Tokyo, Japan, and St. Jude Children’s Research Hospital, USA, explored how age-related stress affects HSCs. They focused on the receptor-interacting protein kinase 3 (RIPK3)-mixed lineage kinase like (MLKL) signaling axis, which is typically associated with necroptosis, a form of programmed cell death.

The study was led by Dr. Masayuki Yamashita, an Assistant Member at St. Jude Children’s Research Hospital, who, at the time of the investigation, was an Assistant Professor at The Institute of Medical Science, The University of Tokyo. Co-authors included Dr. Atsushi Iwama from The Institute of Medical Science, The University of Tokyo, and Dr. Yuta Yamada from St. Jude Children’s Research Hospital, who was a graduate student at The Institute of Medical Science, The University of Tokyo.

A Surprising Discovery About MLKL

The research began with an unexpected observation. Dr. Yamashita explains, “We discovered an unexpected phenotype in HSCs of MLKL-knockout mice repeatedly treated with 5-fluorouracil, where aging-associated functional changes were markedly attenuated despite no detectable difference in HSC death, prompting us to investigate whether this pathway might induce functional changes beyond cell death.”

This finding suggested that MLKL might influence stem cell aging without actually killing the cells. That idea became central to the study, which was published in Volume 17 of Nature Communications on April 6, 2026.

How Scientists Tested the Mechanism

To explore this possibility, the researchers used several types of genetically engineered mice, including wild-type, MLKL-deficient, and RIPK3-deficient models. They also used specialized reporter mice designed to detect MLKL activation using a Förster resonance energy transfer-based biosensor.

The mice were exposed to different stress conditions that mimic aging, such as inflammation, replication stress, and oncogenic stress. To measure how well HSCs functioned, the team relied mainly on bone marrow transplantation, which tests the ability of stem cells to rebuild the blood system.

Additional techniques provided deeper insights, including flow cytometry, ex vivo expansion, RNA-seq, assay for transposase-accessible chromatin-seq, high-resolution imaging, metabolic testing, and detailed studies of mitochondria. Together, these approaches allowed the researchers to examine how MLKL affects HSCs at multiple levels.

Mitochondrial Damage Without Cell Death

The results revealed a previously unknown role for MLKL in stem cell aging. Although MLKL is usually linked to cell death, its activation in HSCs did not increase cell death or reduce cell numbers. Instead, it acted in a different way.

When activated under stress, MLKL briefly moved to the mitochondria, the structures that generate energy within cells. There, it caused damage by lowering membrane potential, altering mitochondrial structure, and reducing energy production. These effects led to key features of aging in HSCs, including reduced ability to renew themselves, decreased production of lymphoid cells, and a shift toward myeloid cell output.

Blocking MLKL Preserves Stem Cell Function

When MLKL was removed or inactivated, many of these problems were significantly reduced. HSCs lacking MLKL retained their ability to regenerate, produced healthier immune cells, showed less DNA damage, and maintained better mitochondrial function. These benefits were seen even in older animals or under stressful conditions.

Notably, these improvements occurred without major changes in gene expression or chromatin accessibility. This suggests that MLKL influences aging through processes that occur after gene activity, particularly at the level of cellular structures like mitochondria, rather than through changes in DNA regulation or inflammation.

Implications for Aging and Future Therapies

The findings point to a common pathway that connects various types of cellular stress to mitochondrial damage and stem cell aging. By identifying MLKL as a key link in this process, the study offers new insight into how aging affects the blood system.

Dr. Yamashita emphasizes, “In the longer term, this research could lead to therapies that preserve the function of hematopoietic stem cells, ultimately improving recovery and long-term health for patients undergoing chemotherapy, radiation, or transplantation. By revealing how non-lethal activation of cell-death pathways drives stem cell aging, these findings may inspire new classes of mitochondrial-protective or necroptosis-modulating drugs.”

A New Understanding of Stem Cell Aging

Overall, the study reveals that MLKL plays an important role in stem cell aging without causing cell death. Instead, it responds to stress by damaging mitochondria and weakening HSC function over time. This discovery challenges traditional views of necroptosis-related proteins and opens new possibilities for slowing or preventing age-related decline in the blood and immune systems.