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Our study found that palmitic acid (PA) inhibited colon cancer cell viability <jats:italic>in\u2009vitro<\/jats:italic> and <jats:italic>in\u2009vivo<\/jats:italic>, in conjunction with an accumulation of reactive oxygen species and lipid peroxidation. The ferroptosis inhibitor Ferrostatin\u20101 but not Z\u2010VAD\u2010FMK (a pan\u2010caspase inhibitor), Necrostatin\u20101 (a potent necroptosis inhibitor), or CQ (a potent inhibitor of autophagy), rescued the cell death phenotype induced by PA. Subsequently, we verified that PA induces ferroptotic cell death through excess iron as cell death was inhibited by iron chelator deferiprone (DFP), while it was exacerbated by a supplement of ferric ammonium citrate. Mechanistically, PA affects intracellular iron content by inducing endoplasmic reticulum (ER) stress leading to ER calcium release and regulating transferrin (TF) transport through increasing cytosolic calcium levels. Furthermore, we observed that cells with high expression of CD36 were more vulnerable to PA\u2010induced ferroptosis. Altogether, our findings reveal that PA engages in anti\u2010cancer properties by activating ER stress\/ER calcium release\/TF\u2010dependent ferroptosis, and PA might serve as a compound to activate ferroptosis in colon cancer cells with high CD36 expression.<\/jats:p>","DOI":"10.1111\/febs.16772","type":"journal-article","created":{"date-parts":[[2023,3,12]],"date-time":"2023-03-12T22:19:45Z","timestamp":1678659585000},"page":"3664-3687","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":93,"title":["Palmitic acid\u2010induced ferroptosis via CD36 activates ER stress to break calcium\u2010iron balance in colon cancer cells"],"prefix":"10.1111","volume":"290","author":[{"given":"Hao","family":"Kuang","sequence":"first","affiliation":[{"name":"Department of Radiation and Medical Oncology, Zhongnan Hospital Wuhan University  China"},{"name":"Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital Wuhan University  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