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M4 demonstrated selective cytotoxicity against TNBC cells, inducing apoptosis and significantly reducing tumour progression and pulmonary metastasis in a 4\u2009T1 orthotopic mouse model at doses lower than paclitaxel. Mechanistic investigations revealed that M4 directly targets heat shock protein 70 (HSP70) by binding to its ATPase domain, triggering lysosomal dysfunction characterized by pH neutralization, reduced acid sphingomyelinase activity, lipid accumulation, and cathepsin leakage. These alterations led to disruption of lysosomal function leading to impaired autophagic degradation, as evidenced by the accumulation of autophagosomes and increased levels of LC3\u2010II\/p62. Knockdown of the HSP70 gene abolished M4\u2010induced lysosomal damage and its anti\u2010TNBC effects, confirming HSP70 as the functional target of M4. Furthermore, inhibition of HSP70 suppressed TNBC metastasis by regulating autophagy\u2010mediated epithelial\u2010mesenchymal transition and stemness. M4 demonstrated selective cytotoxicity against TNBC cells, induced apoptosis, and significantly inhibited tumour progression and pulmonary metastasis in a 4\u2009T1 orthotopic mouse model at doses lower than those of paclitaxel. The combination of M4 and paclitaxel showed synergistic anti\u2010TNBC efficacy both in\u00a0vitro and in\u00a0vivo, effectively counteracting chemotherapy\u2010induced HSP70 upregulation and autophagic activation. The study not only identifies M4 as a promising therapeutic candidate but also validates HSP70\u2010targeted therapy as an effective combinatorial strategy with conventional chemotherapy for the treatment of TNBC.<\/jats:p>","DOI":"10.1111\/cpr.70222","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T22:21:04Z","timestamp":1777501264000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Curcumin\u2010Derived\n                    <scp>HSP70<\/scp>\n                    Inhibitor Disrupts Lysosomal Function to Suppress Triple\u2010Negative Breast Cancer Progression"],"prefix":"10.1111","volume":"59","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0861-6726","authenticated-orcid":false,"given":"Zijian","family":"Li","sequence":"first","affiliation":[{"name":"School of Integrative Medicine Nanjing University of Chinese Medicine  Nanjing China"},{"name":"State Key Laboratory of 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