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Cell Dev. Biol."],"abstract":"<jats:p>Metabolic dysfunction-associated steatohepatitis (MASH) is increasingly recognized as a disorder of inter-organelle communication, in which the lipid droplet (LD)\u2013mitochondria interface serves as a central metabolic hub. Under physiological conditions, this interface couples LD lipolysis to mitochondrial \u03b2-oxidation, ensuring that fatty-acid release matches energy demand. In MASH, chronic nutrient excess disrupts this coupling, driving the accumulation of lipotoxic metabolites, activating innate immune pathways, and perpetuating hepatocellular injury and inflammation. Among the proteins proposed to operate at this LD-mitochondria interface, hydroxysteroid 17\u03b2-dehydrogenase 13 (HSD17B13) has emerged as a particularly compelling candidate. A loss-of-function human genetic variant is associated with reduced risk of chronic liver disease, motivating therapeutic development; however, whether HSD17B13 directly governs physical organelle apposition or merely influences lipid flux remains unresolved, highlighting a key gap between human genetic evidence and experimental models. This review synthesizes current understanding of the molecular organization of the LD-mitochondria axis, critically examines the proposed scaffolding and enzymatic functions of HSD17B13, and discusses the therapeutic potential of restoring organelle communication as a unified strategy in MASH. We conclude that targeting inter-organelle interfaces, rather than isolated metabolic reactions, offers a genetically supported and mechanistically rational path forward.<\/jats:p>","DOI":"10.3389\/fcell.2026.1912237","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T05:52:58Z","timestamp":1784699578000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Mitochondrial dysfunction and lipid droplet dynamics in MASH: HSD17B13 as a therapeutic target"],"prefix":"10.3389","volume":"14","author":[{"given":"Shanzab","family":"Noor","sequence":"first","affiliation":[{"name":"Department of Pathophysiology and Pathology, Shenzhen University Medical School","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Shenzhen University Medical School","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology and Pathology, Shenzhen University Medical School","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1096","DOI":"10.1056\/NEJMoa1712191","article-title":"A protein-truncating HSD17B13 variant and protection from chronic liver disease","volume":"378","author":"Abul-Husn","year":"2018","journal-title":"N. 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