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The increasing global prevalence of non-alcoholic fatty liver disease (NAFLD) underscores the importance of exploring novel therapeutic agents such as Gypenoside XLIX. NAFLD pathogenesis involves lipotoxicity, oxidative stress, and mitochondrial dysfunction, in which mitochondria-associated endoplasmic reticulum membranes (MAMs) play a critical role in organelle communication, calcium signaling, and lipid metabolism. This narrative review summarizes current evidence indicating that Gypenoside XLIX may modulate oxidative stress, restore mitochondrial membrane potential, and regulate calcium homeostasis, thereby indirectly influencing MAM integrity and function. These effects can reduce lipid accumulation, improve hepatocellular metabolism, and attenuate inflammatory responses. This review evaluates the mechanistic impact and function of Gypenoside XLIX on MAM integrity and its effects on NAFLD. However, there is limited direct experimental evidence linking Gypenoside XLIX to MAM regulation, and further studies are required to validate its mechanisms and therapeutic potential in clinical settings.<\/jats:p>","DOI":"10.3390\/molecules31081325","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T16:30:36Z","timestamp":1776443436000},"page":"1325","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Gypenoside XLIX and Mitochondria-Associated ER Membranes in Non-Alcoholic Fatty Liver Disease: Mechanistic Insights and Emerging Perspectives"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-7570-2767","authenticated-orcid":false,"given":"Xinyi","family":"Kwan","sequence":"first","affiliation":[{"name":"Department of Traditional Chinese Medicine, School of Medicine, Xiamen University, Xiamen 361102, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2728-6726","authenticated-orcid":false,"given":"Muhammad Shahzad","family":"Aslam","sequence":"additional","affiliation":[{"name":"Department of Traditional Chinese Medicine, School of Medicine, Xiamen University, Xiamen 361102, China"},{"name":"School of Traditional Chinese Medicine, Xiamen University Malaysia, Sepang 43900, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiqing","family":"Liang","sequence":"additional","affiliation":[{"name":"Hepatology Unit, Xiamen Hospital of Traditional Chinese Medicine, Xiamen 361009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4727-5135","authenticated-orcid":false,"given":"Shaodong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Traditional Chinese Medicine, School of Medicine, Xiamen University, Xiamen 361102, China"},{"name":"School of Traditional Chinese Medicine, Xiamen University Malaysia, Sepang 43900, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"242","DOI":"10.3746\/pnf.2025.30.3.242","article-title":"Kaempferol Inhibits Lipid Accumulation in HepG2 Cells through AMPK-Mediated Autophagy","volume":"30","author":"Park","year":"2025","journal-title":"Prev. 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