{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T10:49:36Z","timestamp":1791370176604,"version":"4.3.1"},"reference-count":64,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Excessive hepatocyte apoptosis triggered by toxic bile acids is the core pathological event of cholestasis, and the direct target of luteolin (Lut), the major bioactive constituent of\n                      <jats:italic>Siphonostegia chinensis<\/jats:italic>\n                      Benth., for this protective effect remains unclear. This study aims to elucidate how Lut suppresses hepatocyte apoptosis and ameliorates cholestatic liver injury.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A murine cholestasis model was induced by \u03b1-naphthylisothiocyanate (ANIT), and the hepatocyte apoptotic pathways were validated in glycochenodeoxycholic acid (GCDCA)-treated HepG2 cells. Liver tissue pathological changes were assessed via hematoxylin-eosin (HE) histological staining. Network pharmacology paired with supplementary RNA sequencing (RNA-seq) was used to screen candidate pathways contributing to Lut\u2019s anti-cholestatic effects. Quantitative real-time PCR, Western blotting and Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) immunostaining were jointly utilized to assess apoptotic levels in liver parenchymal cells. Additionally, surface plasmon resonance (SPR) coupled with molecular docking simulations was adopted to clarify the direct binding profile of Lut.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Lut treatment markedly ameliorated serum biochemical indices and liver histopathological lesions in ANIT-exposed mice. Meanwhile, oxidative stress was alleviated, bile acid transporters were restored, inflammatory cytokines declined, and hepatocyte apoptosis was suppressed. Network pharmacology combined with RNA-seq predicted that Lut alleviates cholestasis through the Phosphatidylinositol 3-kinase\/Protein Kinase B (PI3K\/AKT)-mediated anti-apoptotic pathway. This hypothesis was further supported by TUNEL, Western blotting, and qRT-PCR analyses, which indicated that Lut could activate the PI3K\/AKT, and then suppress hepatocyte apoptosis in cholestasis. SPR analysis revealed a concentration-dependent direct interaction between Lut and PI3K with a kinetic KD of 9.036 \u00d7 10\n                      <jats:sup>\u22125<\/jats:sup>\n                      \u00a0M, and molecular docking revealed a plausible binding mode within the kinase domain. Additionally, the anti-apoptotic effect of Lut was largely abolished when PI3K was inhibited by LY294002\n                      <jats:italic>in vitro<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This study is the first to confirm that Lut directly targets PI3K to initiate the PI3K\/AKT signaling cascade, and thereby suppresses bile acid-induced hepatocyte apoptosis. These findings refine the mechanistic understanding of Lut\u2019s hepatoprotective action from general antioxidant activity to target-specific anti-apoptotic signaling, and provide a molecular explanation for the traditional use of\n                      <jats:italic>S. chinensis<\/jats:italic>\n                      Benth. for the treatment of damp-heat jaundice.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1930755","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T09:51:31Z","timestamp":1791366691000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Luteolin protects against cholestasis by suppressing hepatocyte apoptosis through direct PI3K binding and AKT activation"],"prefix":"10.3389","volume":"17","author":[{"given":"Xingliang","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingchong","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyan","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Second Affiliated Hospital of Shandong First Medical University","place":["Tai\u2019an, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peixu","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Emergency, Zhangjiagang First People\u2019s Hospital","place":["Zhangjiagang, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Dalian No.3 People\u2019s Hospital","place":["Dalian, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sipu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaopei","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"D789","DOI":"10.1093\/nar\/gku1205","article-title":"OMIM.org: Online mendelian inheritance in man (OMIM\u00ae), an online catalog of human genes and genetic disorders","volume":"43","author":"Amberger","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"2362","DOI":"10.1038\/s41467-020-16092-0","article-title":"Hepatocyte mitochondria-derived danger signals directly activate hepatic stellate cells and drive progression of liver fibrosis","volume":"11","author":"An","year":"2020","journal-title":"Nat. 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