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In this study, we investigate the critical role of organellar Ca\n                    <jats:sup>2+<\/jats:sup>\n                    disturbance on defective autophagy and \u03b2 cell lipotoxicity. Palmitate, a saturated fatty acid, induced perilysosomal Ca\n                    <jats:sup>2+<\/jats:sup>\n                    elevation, sustained mTOR complex 1 (mTORC1) activation on the lysosomal membrane, suppression of the lysosomal transient receptor potential mucolipin 1 (TRPML1) channel, and accumulation of undigested autophagosomes in \u03b2 cells. These Ca\n                    <jats:sup>2+<\/jats:sup>\n                    aberrations with autophagy defects by palmitate were prevented by an mTORC1 inhibitor or a mitochondrial superoxide scavenger. To alleviate perilysosomal Ca\n                    <jats:sup>2+<\/jats:sup>\n                    overload, strategies such as lowering extracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    , employing voltage-gated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    channel blocker or ATP-sensitive K\n                    <jats:sup>+<\/jats:sup>\n                    channel opener, effectively abrogated mTORC1 activation and preserved autophagy. Furthermore, redirecting perilysosomal Ca\n                    <jats:sup>2+<\/jats:sup>\n                    into the endoplasmic reticulum (ER), with an ER Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ATPase activator, restored TRPML1 activity, promoted autophagic flux, and improved survival of \u03b2 cells exposed to palmitate-induced lipotoxicity. Our findings suggest oxidative stress\/Ca\n                    <jats:sup>2+<\/jats:sup>\n                    overload\/mTORC1 pathway involvement in TRPML1 suppression and defective autophagy during \u03b2 cell lipotoxicity. Restoring perilysosomal Ca\n                    <jats:sup>2+<\/jats:sup>\n                    homeostasis emerges as a promising therapeutic strategy for metabolic diseases.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.192827","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T17:01:17Z","timestamp":1762880477000},"source":"Crossref","is-referenced-by-count":8,"title":["Palmitate impairs autophagic degradation via oxidative stress\/perilysosomal Ca2+ overload\/mTORC1 activation pathway in pancreatic \u03b2 cells"],"prefix":"10.1172","volume":"10","author":[{"given":"Ha Thu","family":"Nguyen","sequence":"first","affiliation":[{"name":"Department of Physiology,"},{"name":"Mitohormesis Research Center,"},{"name":"Department of Global Medical Science, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luong Dai","family":"Ly","sequence":"additional","affiliation":[{"name":"Department of Physiology,"},{"name":"Mitohormesis 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