Xueqiang Wang, Mengqi Zeng, Cunxiao Sun, Yuhan Gou, Zhaode Feng, Weiqiang Lv, Chaoying Yan, Hansen Wu, Pengfei Zhang, Jie Xu, Ke Cao, Hao Li, Mingge Ding, Zhongbo Liu, Xing Zhang, Jiankang Liu, Xuan Zou, Zhihui Feng
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.