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Obesity is commonly associated with cardiovascular disease. Autophagy preserves heart function in response to various stresses. Pirfenidone (PFD) is an antifibrotic and anti-inflammatory drug. However, its effects on the regulation of metabolic hormones and cardiac autophagy in MASH have not been investigated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Male C57BL\/6J mice were fed a high-fat\/high-carbohydrate (HFHC) diet for 16 weeks to induce obesity and MASH. From week 8, a subgroup received PFD (300\u00a0mg\/kg\/day) via gavage. In vitro, H9c2 cardiomyocytes were exposed to glucolipotoxicity to simulate metabolic stress. Serum metabolic hormones, cardiac histology, microarray analysis, and autophagy-related mRNA and protein levels were analyzed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      PFD treatment restored metabolic hormone balance and promoted cardiac autophagy in obese MASH mice. Mechanistically, PFD upregulated p-AMPK protein levels (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.05), reversing the dysregulation of autophagy-related proteins both in vivo and in glucolipotoxicity-exposed H9c2 cells. Concurrently, PFD prevented systemic insulin resistance (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.001), hepatic steatosis (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.001), and liver damage (ALT\/AST,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.05). In cardiac tissue, PFD attenuated metabolic stress-induced hypertrophy (\n                      <jats:italic>Nppa\/Nppb<\/jats:italic>\n                      mRNA), inflammation (\n                      <jats:italic>Tnf<\/jats:italic>\n                      ,\n                      <jats:italic>Il6<\/jats:italic>\n                      ,\n                      <jats:italic>Adgre1<\/jats:italic>\n                      , and\n                      <jats:italic>Ccl2<\/jats:italic>\n                      mRNA,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.05), and fibrosis (\n                      <jats:italic>Tgfb1<\/jats:italic>\n                      ,\n                      <jats:italic>Col1a1<\/jats:italic>\n                      , and\n                      <jats:italic>Col3a1<\/jats:italic>\n                      mRNA,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.05).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Pirfenidone has cardioprotective effects in obesity-associated MASH by restoring metabolic hormone levels and activating autophagy via p-AMPK signaling. These findings suggest a potential translational therapeutic strategy for treating cardiovascular complications in MASH.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12967-026-08828-1","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T03:26:55Z","timestamp":1787110015000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pirfenidone restores metabolic hormones and cardiac autophagy via p-AMPK in MASH"],"prefix":"10.1186","volume":"24","author":[{"given":"Daniel","family":"L\u00f3pez-Cifuentes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Sandoval-Rodr\u00edguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebeca","family":"Escutia-Guti\u00e9rrez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Armendariz-Borunda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0276-0428","authenticated-orcid":false,"given":"Jorge","family":"Guti\u00e9rrez-Cuevas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"8828_CR1","doi-asserted-by":"crossref","unstructured":"Gutierrez-Cuevas J, Sandoval-Rodriguez A, Meza-Rios A, Monroy-Ramirez HC, Galicia-Moreno M, Garcia-Banuelos J, Santos A, Armendariz-Borunda J. 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