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This study investigated the function and mechanisms of gasotransmitters and autophagy in the metformin-induced protection against ischemia\/reperfusion injury (I\/RI). According to measurements of serum hepatic function indicators and histopathological evaluation, metformin protected against hepatic I\/RI-induced impairment of liver function and structure. In addition, metformin inhibited hepatic I\/RI-induced hepatic oxidative stress, nitrosative stress, inflammation, and apoptosis. Also, it suppressed hepatic I\/RI-induced decrease in hepatic heme oxygenase-1 (HO-1) and hydrogen sulfide (H\n                    <jats:sub>2<\/jats:sub>\n                    S) levels and increase in nitric oxide (NO) production. Furthermore, metformin inhibited hepatic I\/RI-induced decrease in protein expressions of endothelial NO synthase (eNOS), HO-1, cystathionine \u03b3-lyase (CSE), and Beclin-1 and increase in the protein expression of inducible NO synthase (iNOS) in the liver tissue. Co-administration of the NO biosynthesis inhibitor, L-NAME, carbon monoxide(CO)-releasing molecule-A\n                    <jats:sub>1<\/jats:sub>\n                    (CORM-A\n                    <jats:sub>1<\/jats:sub>\n                    ), the H\n                    <jats:sub>2<\/jats:sub>\n                    S donor, NaHS, or the autophagy stimulator, rapamycin (RAPA), enhanced all effects of metformin. The NO donor, L-arginine, the CO biosynthesis inhibitor, zinc protoporphyrin, the H\n                    <jats:sub>2<\/jats:sub>\n                    S biosynthesis inhibitor, DL-propargylglycine, or the autophagy inhibitor, chloroquine (CQ), antagonized the effects of metformin. These findings reveal, for the first time, that increasing CO, H\n                    <jats:sub>2<\/jats:sub>\n                    S, and autophagy levels with subsequent decreasing NO level play a critical role in metformin's protective action against hepatic I\/RI. The ability of L-NAME, CORM-A\n                    <jats:sub>1<\/jats:sub>\n                    , NaHS, and RAPA to boost metformin\u2019s protective effect in hepatic I\/RI may positively be attributed to their ability to lower hepatic oxidative stress, nitrosative stress, inflammation, and apoptosis.\n                  <\/jats:p>","DOI":"10.1007\/s00210-025-03837-1","type":"journal-article","created":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T04:00:32Z","timestamp":1738814432000},"page":"9177-9198","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Novel mechanistic insights of the potential role of gasotransmitters and autophagy in the protective effect of metformin against hepatic ischemia\/reperfusion injury in rats"],"prefix":"10.1007","volume":"398","author":[{"given":"Ahmed O.","family":"Abdel-Zaher","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwa H.","family":"Bakr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yomna H.","family":"Gad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alaa T.","family":"Abdelhafez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,6]]},"reference":[{"key":"3837_CR1","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1007\/s00210-016-1330-7","volume":"390","author":"AA Abdelsameea","year":"2017","unstructured":"Abdelsameea AA, Abbas NA, Abdel Raouf SM (2017) Liraglutide attenuates partial warm ischemia-reperfusion injury in rat livers. 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