{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T06:12:20Z","timestamp":1789193540021,"version":"build-2803163510"},"reference-count":28,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2024,5,28]],"date-time":"2024-05-28T00:00:00Z","timestamp":1716854400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Gastro and Hepatol"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background and Aim<\/jats:title><jats:p>Hydronidone (HDD) is a novel pirfenidone derivative developed initially to reduce hepatotoxicity. Our previous studies in animals and humans have demonstrated that HDD treatment effectively attenuates liver fibrosis, yet the underlying mechanism remains unclear. This study aimed to investigate whether HDD exerts its anti\u2010fibrotic effect by inducing apoptosis in activated hepatic stellate cells (aHSCs) through the endoplasmic reticulum stress (ERS)\u2010associated mitochondrial apoptotic pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>)\u2010 and 3,5\u2010diethoxycarbonyl\u20101,4\u2010dihydrocollidine (DDC)\u2010induced liver fibrosis models were used for in vivo studies. In vitro studies were conducted using the human hepatic stellate cell line LX\u20102. The apoptotic effect of HDD on aHSCs was examined using TUNEL and flow cytometry assays. The small interfering RNA (siRNA) technique was employed to downregulate the expression of interest genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>HDD treatment significantly promoted apoptosis in aHSCs in both the CCl<jats:sub>4<\/jats:sub>\u2010 and DDC\u2010induced liver fibrosis in mice and LX\u20102 cells. Mechanistic studies revealed that HDD triggered ERS and subsequently activated the IRE1\u03b1\u2010ASK1\u2010JNK pathway. Furthermore, the influx of cytochrome c from the mitochondria into the cytoplasm was increased, leading to mitochondrial dysfunction and ultimately triggering apoptosis in aHSCs. Notably, inhibition of IRE1\u03b1 or ASK1 by siRNA partially abrogated the pro\u2010apoptotic effect of HDD in aHSCs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The findings of both in vivo and in vitro studies suggest that HDD induces apoptosis in aHSCs via the ERS\u2010associated mitochondrial apoptotic pathway, potentially contributing to the amelioration of liver fibrosis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jgh.16635","type":"journal-article","created":{"date-parts":[[2024,5,28]],"date-time":"2024-05-28T13:49:53Z","timestamp":1716904193000},"page":"1695-1703","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Hydronidone induces apoptosis in activated hepatic stellate cells through endoplasmic reticulum stress\u2010associated mitochondrial apoptotic 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