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Here, we identify lipase maturation factor 2 (LMF2), a previously uncharacterized gene in human cancer, as a novel oncogenic driver that promotes tumor growth, metastasis, and resistance to capecitabine in TNBC both in vitro and in vivo. Mechanistically, LMF2 localizes predominantly to the endoplasmic reticulum membrane and is targeted for autophagic degradation mediated by the autophagy receptor NBR1. Valosin\u2010containing protein (VCP) counteracts this process to stabilize LMF2 by impeding the LMF2\u2010NBR1 interaction, and pharmacological inhibition of VCP effectively suppressed LMF2\u2010driven TNBC progression and capecitabine resistance. LMF2, in turn, disrupts the interaction between the autophagy receptor NDP52 and HMGCS1, the rate\u2010limiting enzyme in cholesterol biosynthesis, thereby shielding HMGCS1 from autophagic degradation and enhancing cholesterol production. Importantly, re\u2010expression of HMGCS1 or exogenous cholesterol supplementation partially rescued the malignant and chemoresistant phenotypes impaired by LMF2 depletion. Clinically, the VCP\u2010LMF2\u2010HMGCS1 axis is significantly co\u2010upregulated in TNBC patient specimens. Collectively, these findings unveil a previously unrecognized VCP\u2010LMF2\u2010HMGCS1 regulatory axis that drives TNBC progression and chemoresistance, and identify LMF2 as a promising therapeutic target for this recalcitrant disease.<\/jats:p>","DOI":"10.1002\/advs.78301","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T05:13:13Z","timestamp":1792559593000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["VCP\u2010Regulated LMF2 Stabilizes the Cholesterol Biosynthesis Enzyme HMGCS1 to Drive Cancer Progression and Confer Capecitabine Resistance in Triple\u2010Negative Breast Cancer"],"prefix":"10.1002","author":[{"given":"Qian","family":"Zhao","sequence":"first","affiliation":[{"name":"Cancer Institute Fudan University Shanghai Cancer Center Department of Oncology Shanghai Medical College Fudan University  Shanghai China"},{"name":"Key Laboratory of Breast Cancer in Shanghai 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