Stress Chemical NPY Revealed as Hidden Driver of Liver Scarring

A stress-related signaling molecule produced by nerves inside the liver appears to play a far more active role in liver scarring than scientists previously appreciated. In a study published in Cellular and Molecular Life Sciences, a team based at Tangdu Hospital of the Fourth Military Medical University in Xi’an, China, reports that neuropeptide Y, or NPY, a small protein messenger long associated with appetite, blood vessel constriction, and the body’s stress response, acts as a molecular switch that pushes liver macrophages into inflammatory and scar-promoting states. The work, led by Qiang Lin and Xuyang Zheng, who contributed equally, with corresponding authors Jingjie Wang, Jikai Yin, and Zhenxiong Liu, traces the entire signaling chain from nerve ending to immune cell to collagen-depositing scar tissue, and suggests that blocking this pathway could open a new front against hepatic fibrosis.

Hepatic fibrosis is the accumulation of excess extracellular matrix, chiefly collagen, that follows chronic liver injury from causes such as viral hepatitis, alcohol use, fatty liver disease, and cholestatic disorders. Left unchecked, it progresses to cirrhosis and dramatically raises the risk of hepatocellular carcinoma. At the center of the scarring process are hepatic stellate cells, quiescent vitamin A-storing cells that, when activated by inflammatory cues, transform into myofibroblast-like cells that pump out matrix proteins. The immune microenvironment surrounding these cells, particularly the behavior of macrophages, largely determines whether injury resolves or spirals into permanent scarring. Macrophages are famously plastic: they can polarize toward a classically activated M1 state, marked by production of tumor necrosis factor-alpha and interleukin-1 beta, or toward an alternatively activated M2 state, associated with transforming growth factor beta and tissue remodeling. Both extremes, paradoxically, can feed fibrosis, one by fueling inflammation and the other by driving matrix deposition.

What the new study adds is a nervous system connection to this immunological drama. The researchers began by examining liver tissue from cirrhotic and non-cirrhotic human subjects, with informed consent and ethical approval from Tangdu Hospital, and then modeled fibrosis in mice using two complementary approaches: repeated intraperitoneal injection of carbon tetrachloride, a hepatotoxin that causes oxidative injury, and a 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet, which induces cholestatic damage. Across both human samples and both mouse models, NPY levels rose in fibrotic livers. Crucially, the source of that NPY was not the liver cells themselves but intrahepatic sympathetic nerves, identified through markers such as tyrosine hydroxylase. The finding places the sympathetic nervous system, the branch that mediates fight-or-flight responses, in direct molecular contact with the liver’s immune landscape.

The team next asked which cells were listening. NPY signals through a family of G protein-coupled receptors, and the investigators mapped their distribution carefully. Two of them, NPY1R and NPY2R, were significantly increased in fibrotic liver and localized specifically to hepatic macrophages, while the related NPY4R and NPY5R did not show the same pattern. This receptor specificity matters, because it narrows a broad neuropeptide signal down to a defined cellular target and suggests that the macrophage is the critical relay station between sympathetic nerve activity and fibrogenesis.

To test causality rather than mere correlation, the researchers turned to genetics and gene silencing. In NPY-knockout mice subjected to the fibrosis protocols, liver injury, collagen deposition, and inflammation were all significantly reduced. Flow cytometry and molecular profiling of the animals’ macrophages revealed that the deletion suppressed both M1 and M2 polarization, indicating that NPY was not simply tipping the balance between the two states but amplifying the entire profibrotic immune program. When the team silenced NPY1R or NPY2R in the liver in vivo using adeno-associated virus vectors, the protective phenotype was recapitulated, confirming that the receptors were the necessary conduits for NPY’s fibrogenic effects.

The mechanistic heart of the paper lies in the downstream signaling dissection, performed in vitro with bone marrow-derived macrophages. The researchers found that NPY engages a PI3K-dependent cascade in both polarization directions, but the pathways diverge at a key kinase node. For M1 polarization, NPY acting through NPY1R and NPY2R activates the PI3K-PAK1-c-Jun axis, with c-Jun, a component of the AP-1 transcription factor complex, driving the inflammatory gene program. For M2 polarization, the signal instead flows through PI3K-PAK1 to RSK, a ribosomal S6 kinase, promoting the alternative activation program. Blocking the corresponding receptors or the downstream kinases pharmacologically in vitro abolished these effects, allowing the authors to draw a solid, experimentally validated map from neuropeptide to receptor to kinase to transcription factor to macrophage phenotype.

The final link in the chain connects macrophages back to stellate cells. Polarized macrophages release a cocktail of profibrotic cytokines, including TNF-alpha, IL-1 beta, TGF-beta, and platelet-derived growth factor BB, which are well-established activators of hepatic stellate cells. By supercharging both macrophage states, NPY effectively raises the volume of the profibrotic conversation between immune cells and matrix-producing cells. The authors are careful to distinguish what has been proven from what remains plausible: the receptor-PI3K-PAK1 cascades are experimentally validated, whereas a direct NPY effect on stellate cells and the precise macrophage-stellate cell crosstalk remain putative, unvalidated interactions in their model. That transparency is a useful reminder of where the science currently stands.

The therapeutic implications are considerable. Current antifibrotic options are limited, and most strategies target downstream consequences of injury rather than upstream regulatory circuits. If sympathetic nerve-derived NPY is a genuine driver of fibrogenesis, then NPY1R and NPY2R become attractive drug targets, and receptor antagonists, some of which have already been developed for metabolic and cardiovascular research, could in principle be repurposed or refined. The dual role of NPY in pushing macrophages toward both inflammatory and profibrotic states suggests that receptor blockade might dampen fibrosis through two mechanisms simultaneously. At the same time, the systemic importance of NPY in appetite regulation, vascular tone, and stress physiology means that any clinical strategy would need to navigate a narrow therapeutic window, likely favoring targeted delivery to the liver or selective peripheral receptor antagonism over systemic neuropeptide depletion.

The study also contributes to a rapidly growing appreciation of neuroimmune crosstalk in chronic disease. The idea that nerves do more than transmit sensation and regulate tone, that they actively sculpt local immune responses through neuropeptide release, has gained traction in fields ranging from intestinal inflammation to tumor immunology. This work extends that framework to the liver, an organ densely innervated at portal triads and richly supplied by sympathetic fibers, and identifies a concrete molecular itinerary by which neural input becomes fibrotic output. It raises provocative questions about whether chronic stress, which elevates sympathetic outflow and systemic NPY, might modulate fibrosis progression in patients, a hypothesis the current study does not directly test but which its findings make testable.

Caveats remain, as they do in any preclinical study. The mouse models, carbon tetrachloride injury and DDC diet, are established but imperfect proxies for the heterogeneous fibrotic diseases seen in clinics, and the human tissue analysis, while consistent with the animal data, is observational. Whether NPY receptor blockade can safely slow or reverse established fibrosis in patients will require medicinal chemistry, pharmacokinetics, and eventually clinical trials that this paper does not provide. Still, by connecting sympathetic nerves, macrophage polarization, PI3K-MAPK signaling, and stellate cell activation into a single coherent pathway, the Xi’an team has converted a diffuse suspicion that the nervous system matters in liver disease into a specific, targetable hypothesis. For the millions of people living with chronic liver disease worldwide, that specificity is precisely what the field needs.

Subject of Research: Neuroimmune signaling by neuropeptide Y in macrophage polarization and hepatic fibrosis

Article Title: NPY promotes macrophage polarization and hepatic fibrogenesis via PI3K/MAPK-dependent neuroimmune mechanisms

Article References: Lin, Q., Zheng, X., Dou, W., Bai, Q., Liang, S., Kou, Z., Guo, H., Ding, Y., Zhao, S., Wang, J., Yin, J., & Liu, Z. (2026). NPY promotes macrophage polarization and hepatic fibrogenesis via PI3K/MAPK-dependent neuroimmune mechanisms. Cellular and Molecular Life Sciences, 83(1), Article 346. https://doi.org/10.1007/s00018-026-06428-2

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06428-2

Keywords: neuropeptide Y, hepatic fibrosis, macrophage polarization, NPY1R, NPY2R, PI3K signaling, MAPK, sympathetic nervous system, hepatic stellate cells, liver cirrhosis, neuroimmune crosstalk, cytokines