{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T19:02:08Z","timestamp":1785438128405,"version":"3.56.0"},"reference-count":64,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82274386"],"award-info":[{"award-number":["82274386"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82374349"],"award-info":[{"award-number":["82374349"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82274386"],"award-info":[{"award-number":["82274386"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82374349"],"award-info":[{"award-number":["82374349"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"\u201cLong-Yi Scholar\u201d Clinical Science and Technology Innovation Program","award":["PY2026005"],"award-info":[{"award-number":["PY2026005"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Objective: While Sanzi Sijun Formula (SSF) has exhibited preliminary efficacy against metabolic dysfunction-associated steatotic liver disease (MASLD), its mode of action remains undefined. This study therefore aimed to unravel its core therapeutic mechanisms. Methods: UPLC-MS was employed to characterize the major components of SSF. Male C57BL\/6J mice were fed a high-fat diet combined with high-fructose\/glucose drinking water (HFD-HF\/G) for 10 weeks to establish a MASLD model, followed by SSF intervention. After 8-week treatment, body and liver weight, hepatic histopathological alterations, serum levels of lipids, transaminase, and inflammatory cytokines were detected, and transcriptomic sequencing was performed on mouse liver tissues for mechanistic exploration. AML12 hepatocytes stimulated with palmitic acid (PA) were treated with SSF alone or in combination with AMPK or SIRT1 specific inhibitors. RT-qPCR and Western blotting were used to detect the expression or activation levels of AMPK, SIRT1, and key lipid metabolism-related molecules. Results: A total of 77 active components were identified in SSF by UPLC-MS analysis. In MASLD model mice, SSF significantly reduced body and liver weight, serum levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-c), and alanine aminotransferase (ALT), suppressed the pro-inflammatory cytokines including TNF-\u03b1 and IL-6, and elevated adiponectin levels. Histopathological staining demonstrated that SSF effectively alleviated hepatic steatosis, ballooning, and inflammatory cell infiltration. Transcriptomic profiling analysis verified the major regulatory effect of SSF on lipid metabolism and identified the AMPK\/SIRT1 signaling pathway as a potential mechanism. Further experiments confirmed that SSF restored the levels of AMPK\/ACC phosphorylation and SIRT1 expression, thereby modulating downstream lipid metabolism-related genes in liver tissues. In PA-induced AML12 cells, SSF significantly reduced intracellular accumulation of lipid and reactive oxygen species (ROS), which were partially abrogated by the inhibitors of AMPK or SIRT1. Conclusions: SSF exerts prominent effects against MASLD in both in vivo and in vitro models. Modulation of the AMPK\/SIRT1 signaling pathway primarily contributes to its therapeutic mechanism against lipid metabolism disorder and lipotoxic liver injury. These findings provide experimental evidence to support the clinical application of SSF for MASLD treatment.<\/jats:p>","DOI":"10.3390\/ph19081195","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T17:01:46Z","timestamp":1785344506000},"page":"1195","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sanzi Sijun Formula Alleviates Lipotoxic Liver Injury in Metabolic Dysfunction-Associated Steatotic Liver Disease via AMPK\/SIRT1 Signaling Pathway"],"prefix":"10.3390","volume":"19","author":[{"given":"Junyao","family":"Ding","sequence":"first","affiliation":[{"name":"Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Huang","sequence":"additional","affiliation":[{"name":"Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4664-5977","authenticated-orcid":false,"given":"Zhiwei","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yining","family":"Xue","sequence":"additional","affiliation":[{"name":"Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunlong","family":"Hua","sequence":"additional","affiliation":[{"name":"Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2155-8110","authenticated-orcid":false,"given":"Haiyan","family":"Song","sequence":"additional","affiliation":[{"name":"Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiyong","family":"Zheng","sequence":"additional","affiliation":[{"name":"Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S5","DOI":"10.3350\/cmh.2022.0424","article-title":"Non-alcoholic fatty liver disease: Definition and subtypes","volume":"29","author":"Han","year":"2023","journal-title":"Clin. 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