Cells cannot grow indefinitely by simply consuming nutrients. Growth requires a coordinated supply of energy, carbon building blocks and molecular machinery, but it also creates damaged proteins, defective organelles and other waste that must be removed. Autophagy provides one of the cell’s principal quality-control systems. During autophagy, a small membrane structure called a phagophore expands around selected cellular material. The phagophore then closes to form an autophagosome, a double-membraned compartment that delivers its contents to lysosomes for degradation and recycling. This process can supply nutrients during starvation, remove potentially harmful debris and help cells recover from stress. Yet autophagy must be carefully controlled. Too little can allow damage to accumulate, while excessive or mistimed activity can consume essential components. The new findings place PGAM1 at an early decision point in this process, where metabolic status and autophagy initiation can be coordinated rather than regulated as separate cellular programs.

PGAM1 has traditionally been understood as a glycolytic enzyme. In glycolysis, a chain of reactions converts glucose into pyruvate while generating usable energy and producing intermediates that can be diverted into the synthesis of nucleotides, lipids and amino acids. PGAM1 catalyzes the reversible conversion of one phosphorylated sugar intermediate into another, helping maintain the flow of carbon through the pathway. Cancer cells frequently increase glycolytic activity even when oxygen is available, a metabolic pattern associated with rapid biomass production and adaptability. The study shows that PGAM1’s importance extends beyond this catalytic function. When researchers examined complementary yeast and mammalian systems, they found that the protein also acts as a physical organizer for the machinery that initiates autophagy. This distinction is crucial: the same protein can promote growth through its enzyme activity while supporting stress survival through a separate structural role.

The autophagy function of PGAM1 appears to depend on its ability to recruit phosphatidylinositol 3-kinase complex I to the phagophore assembly site. This complex is a central component of the molecular machinery that marks and organizes the membrane where an autophagosome will form. By helping bring the complex to the correct location, PGAM1 effectively licenses the earliest stages of autophagosome biogenesis. Without this recruitment step, the cell may possess the individual ingredients needed for autophagy but fail to assemble them into a functional initiation site. The finding suggests that PGAM1 is not merely associated with autophagy as a downstream consequence of altered metabolism. It operates directly at the point where the autophagic membrane-building program is switched on. In molecular terms, PGAM1 functions as a scaffold: a platform that assembles proteins into a productive complex without necessarily changing those proteins through an enzymatic reaction.

The researchers further found that this role is regulated by phosphorylation mediated by Atg1 in yeast and ULK1 in mammals. These related protein kinases are among the best-known initiators of autophagy, responding to conditions such as nutrient depletion. Phosphorylation changes the behavior of a target protein by adding a phosphate group to specific amino acids, potentially altering its shape, location or binding partners. Under starvation conditions, Atg1 or ULK1-mediated phosphorylation enhances PGAM1’s interaction with Atg14, a component associated with the autophagy-initiation machinery. This provides a direct biochemical route through which stress signals can redirect a glycolytic enzyme toward autophagy control. Rather than treating metabolism and autophagy as independent responses, the mechanism allows a cell to use information about nutrient availability to modify the physical assembly of its recycling apparatus. It also indicates that PGAM1’s checkpoint function is dynamically regulated, becoming especially important when external nutrients are scarce.

Genetic experiments described in the study indicate that PGAM1’s autophagy-regulatory activity is essential and evolutionarily conserved. Conservation across yeast and mammalian systems suggests that the mechanism arose early and has been retained because it solves a fundamental cellular problem: how to maintain growth when nutrients are plentiful and preserve viability when those nutrients disappear. The researchers also found that the autophagy function can be separated genetically from PGAM1’s role in glycolysis. In other words, disrupting the protein’s ability to support autophagy does not simply amount to shutting down its metabolic enzyme activity, and vice versa. This separation strengthens the case that PGAM1 has two distinct molecular identities within the cell. One supports the movement of glucose-derived metabolites through glycolysis; the other helps organize the machinery required to initiate autophagosome formation. Together, the two activities allow cells to match biomass production with quality control and stress tolerance.

That coordination becomes particularly significant in cancer. Tumour cells are under continuous pressure: they must divide rapidly, secure enough nutrients to make new cellular material and survive conditions created by poor blood supply, crowding and fluctuating oxygen or nutrient levels. Increased PGAM1 expression, according to the findings, enhances both glycolytic flux and autophagy capacity. The first effect can provide energy and biosynthetic intermediates for proliferation. The second can help cancer cells recycle internal resources and remove damage when their environment becomes difficult. This combination could give tumour cells a form of metabolic flexibility, allowing them to grow under favorable conditions and endure unfavorable ones. The study reports that disrupting either PGAM1 function markedly impairs tumour growth. That result suggests that cancer cells may depend on the enzyme’s two activities simultaneously, rather than relying only on its established contribution to glycolysis.

The findings could influence how researchers think about targeting metabolic proteins in cancer. A drug designed only to block PGAM1’s catalytic activity might reduce glycolytic output while leaving the protein’s autophagy-scaffolding function intact. Conversely, an intervention that prevents PGAM1 from recruiting autophagy-initiation factors could weaken tumour stress tolerance without necessarily eliminating all glycolytic activity. The study therefore points to a potential therapeutic vulnerability at the interface between metabolism and autophagy. However, the discovery does not by itself establish a treatment or show how such an approach would behave in patients. Autophagy is also essential for normal cells, particularly those exposed to nutrient limitation or other physiological stresses, so broadly suppressing the pathway could carry substantial risks. The significance of the work is instead that it identifies a more precise molecular connection—PGAM1’s interaction with the autophagy machinery—that future research can examine in detail.

More broadly, the study presents cellular survival as a balancing act governed by shared molecular components rather than by isolated pathways. Glycolysis is often described as an energy-producing route, while autophagy is commonly framed as a recycling and quality-control system. PGAM1 shows how those categories can overlap: a protein best known for processing a glycolytic intermediate can also determine whether a membrane structure for autophagy is assembled. Its phosphorylation by Atg1 or ULK1 during starvation places the enzyme within a responsive network that can shift the cell from growth toward maintenance without abandoning metabolism altogether. In cancer, that same integration appears to be exploited, coupling the production of cellular building blocks with the ability to survive stress. By revealing PGAM1 as a metabolic–autophagy checkpoint, the work provides a mechanistic explanation for how cells coordinate proliferation, recycling and resilience—and identifies a molecular junction where the biological logic of healthy adaptation can be repurposed to sustain tumour growth.

The intricacies of the neural circuitry involved in stress responses have long been a focus of neuroscientific inquiry. However, the specific molecular players that fine-tune these complex networks remain incompletely understood. Neurensin-2, encoded by a gene previously identified but sparsely studied in the context of stress physiology, is now thrust into the spotlight. Its expression profiles within key limbic structures—including the hippocampus and prefrontal cortex—hint at a specialized role in balancing excitatory and inhibitory signals during stressful stimuli. This study represents the first comprehensive characterization of the behavioral and neurochemical consequences of ablating Neurensin-2 in vivo.

Through meticulous behavioral assays, the research team systematically evaluated the impact of Neurensin-2 deletion on stress-induced phenotypes. Knockout mice demonstrated a remarkable resistance to chronic stress paradigms that typically precipitate anxiety-like and depressive-like behaviors in wild-type counterparts. Specifically, Neurensin-2 deficient specimens exhibited enhanced exploratory behavior in open field tests and reduced immobility in forced swim assays, classical indicators of lower anxiety and depressive states, respectively. These observations suggest that Neurensin-2 may act as a modulator restraining the brain’s intrinsic adaptive capacity to stress.

At the cellular level, the absence of Neurensin-2 induced significant alterations in synaptic plasticity—an essential mechanism by which neurons encode experience and adapt their signaling. Electrophysiological recordings revealed enhanced long-term potentiation (LTP) in hippocampal slices from knockout mice, indicative of heightened synaptic strength and neural circuit flexibility. This finding dovetails with behavioral data, positing that Neurensin-2 constrains synaptic remodeling under stress, thereby influencing resilience. Notably, the study delineates the downstream signaling cascades affected by Neurensin-2 loss, including modifications in calcium signaling pathways and neurotransmitter release dynamics.

Further probing into molecular changes unveiled a remarkable rewiring of the stress-responsive neurochemical milieu. Neurotransmitter assays indicated upregulated GABAergic transmission alongside dampened glutamatergic excitability in critical brain regions, a balance shift that likely underpins the observed behavioral resilience. The interplay between inhibitory and excitatory neurotransmission is central to emotional regulation circuits; thus, Neurensin-2’s modulation of these systems emerges as a key factor in stress adaptability. These neurochemical adjustments echo existing theories positing enhanced inhibitory control as protective against stress-induced psychopathology.

Importantly, the research team used advanced transcriptomic analyses to map global gene expression changes resulting from Neurensin-2 ablation. The knockout mice displayed differential regulation of genes implicated in stress hormone signaling, neuroinflammation, and synaptic architecture, including notable shifts in corticotropin-releasing hormone (CRH) pathways and microglial activation markers. This comprehensive molecular portrait paints Neurensin-2 as a crucial node interfacing neuroimmune responses with synaptic plasticity, offering a holistic view of the neural adaptations that foster resilience.

From a translational perspective, these findings herald exciting prospects for innovative treatments. By targeting Neurensin-2 or its downstream effectors, future therapies could potentially amplify endogenous resilience mechanisms, offering alternatives to current pharmacological approaches that predominantly aim to alleviate symptoms rather than recalibrate stress response systems. Additionally, this study opens avenues for biomarker development; Neurensin-2 levels or associated signaling components might serve as predictors of vulnerability or treatment response in stress-related disorders.

Crucially, this work emphasizes the importance of integrating genetic and environmental factors in understanding stress resilience. While Neurensin-2 knockout mice display enhanced resilience, their interaction with various stress paradigms underscores the dynamic interplay between genes and experiences. This nuanced understanding aligns with contemporary models advocating for personalized medicine approaches, where individual genetic profiles guide interventions for psychiatric disorders.

The authors also address potential limitations, including the need to verify whether similar mechanisms operate in humans and the extent to which Neurensin-2 modulates other cognitive domains beyond stress responses. Ongoing and future studies employing human-derived neuronal cultures and postmortem analyses will be pivotal in validating translational relevance. Moreover, dissecting Neurensin-2’s role in distinct neuronal subtypes may further refine our grasp of its function within broader neural networks.

Beyond stress resilience, the implications of Neurensin-2 function extend to neurodevelopmental processes and synaptic homeostasis. Given the protein’s localization to synaptic compartments, alterations in its expression or function could conceivably contribute to psychiatric disorders characterized by synaptic dysregulation, such as schizophrenia or bipolar disorder. This broadens the scope of impact, suggesting that Neurensin-2 may be a versatile target for a spectrum of neuropsychiatric conditions.

The methodological rigor of this study, combining state-of-the-art genetic engineering, behavior analysis, electrophysiology, and transcriptomics, sets a new standard for dissecting molecular mechanisms in neuroscience. The integration of multi-modal data affords a comprehensive understanding that transcends reductionist approaches, providing a rich resource for the research community. The codevelopment of behavioral assays tailored to probe nuanced emotional and cognitive traits further strengthens the study’s conclusions.

Moreover, the findings invite a reevaluation of how resilience is conceptualized in biological frameworks. Instead of viewing it as a static trait, this research underscores resilience as a dynamic, modifiable process intimately linked to molecular regulators like Neurensin-2. This perspective could transform therapeutic strategies, pivoting from symptom management toward actively enhancing resilience through targeted molecular interventions.

In summation, the characterization of Neurensin-2 knockout mice reveals a novel, intricate mechanism by which this protein orchestrates stress resiliency via synaptic modulation and neurochemical balancing. By bridging molecular neuroscience with behavioral outcomes, this landmark study offers both theoretical and practical advancements in our understanding of how organisms adapt to adversity. As the mental health burden continues to escalate globally, uncovering such fundamental resilience mechanisms is a crucial step toward more effective and personalized interventions.

As the field moves forward, the challenge will be to translate these compelling preclinical findings into clinical applications. This will require multidisciplinary collaborations spanning molecular biology, psychiatry, and pharmacology. Nevertheless, the promise held by Neurensin-2 modulation as a therapeutic avenue inspires optimism for the future of mental health treatment and resilience enhancement.

Subject of Research: Characterization of Neurensin-2 knockout mice and the molecular and behavioral mechanisms underlying stress resilience.

Article Title: Characterization of Neurensin-2 knockout mice: insights into stress-resilience mechanisms.

Article References:
Hovav, H.C., Kashi, O.Y., Abu Ghanem, Y. et al. Characterization of Neurensin-2 knockout mice: insights into stress-resilience mechanisms. Transl Psychiatry 15, 225 (2025). https://doi.org/10.1038/s41398-025-03448-7

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41398-025-03448-7