Advanced Science· 2026Q1
A Hepatocyte‐to‐Stellate Cell Axis Couples Alternate‐Day Fasting to Liver Fibrosis Resolution via ATG7 S‐Nitrosylation
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- Q1SCImago
- 2026year
Short summary
Alternate-day fasting (ADF) resolves liver fibrosis by enhancing hepatocyte eNOS expression, which produces nitric oxide (NO) that S-nitrosylates ATG7 in hepatic stellate cells (HSCs), thereby preventing HSC activation and fibrosis.
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Key points
- A hepatocyte-to-HSC signaling axis mediated by eNOS restrains HSC activation and liver fibrosis.
- Alternate-day fasting (ADF) enhances hepatocyte eNOS expression, which is crucial for its anti-fibrotic effects.
- ADF leads to NO production that S-nitrosylates ATG7 in HSCs, preventing their transdifferentiation and reducing fibrosis.
- Hepatocyte-specific eNOS deletion abolishes the protective metabolic and anti-fibrotic effects of ADF.
AI-generated from the title and abstract; the full text is not read.
Abstract
ABSTRACT Communication between hepatocytes and hepatic stellate cells (HSCs) is essential for liver homeostasis, yet its potential role in mitigating fibrosis remains largely unexplored. Here, we define a protective signaling axis from hepatocytes to HSCs, mediated by hepatocyte‐expressed eNOS, that restrains HSC activation and fibrotic progression. In human fibrotic liver samples and mouse models, eNOS expression is markedly suppressed, and its hepatocyte‐specific deletion aggravates injury and fibrosis. We further establish that the anti‐fibrotic benefits of alternate‐day fasting (ADF) critically depend on this intercellular pathway. ADF enhanced hepatocyte eNOS expression, and hepatocyte‐specific eNOS knockout abolished the protective metabolic and anti‐fibrotic effects of ADF. Mechanistically, ADF downregulates the mitochondrial chaperone SDHAF4, thereby suspending complex II assembly and promoting eNOS‐derived nitric oxide (NO) production. The resulting NO acts in a paracrine manner on HSCs to induce S‐nitrosylation of ATG7 at cysteine 184, which in turn constraining autophagic flux and preventing HSC transdifferentiation. Our study reveals a fasting‐responsive hepatocyte–stellate cell circuit that protects against liver fibrosis, highlighting the eNOS/NO/ATG7 S‐nitrosylation axis as a tractable therapeutic target.
The authors' abstract, as published at the source. Advanced Science, 2026 · DOI ↗
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Field: Hepatology
HepatologyMedicine