{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T14:10:08Z","timestamp":1774275008933,"version":"3.50.1"},"reference-count":26,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"NIH","doi-asserted-by":"publisher","award":["R01CA262757"],"award-info":[{"award-number":["R01CA262757"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"NIH","doi-asserted-by":"publisher","award":["CA267893"],"award-info":[{"award-number":["CA267893"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Approximately 2\u20134% of all breast cancer cases are inflammatory breast cancer (IBC), an extremely rare and severe subtype of the disease. Current therapies, including chemotherapy, surgery, and radiotherapy, remain insufficient, underscoring the need for novel therapeutic approaches. IBC exhibits elevated basal endoplasmic reticulum (ER) stress, suggesting a potential vulnerability. We recently developed ERX-41, a small molecule that exacerbates ER stress in cancer cells by inhibiting the endoplasmic reticulum-localized function of Lysosomal acid lipase A (LIPA). Here, we evaluated the therapeutic potential of ERX-41 in IBC models. ERX-41 markedly reduced the viability of IBC cells and significantly impaired clonogenic survival while promoting apoptosis. The specificity of ERX-41 was confirmed using LIPA-knockdown and LIPA-knockout cells. RT-PCR-based assays revealed rapid induction of XBP1 splicing within 6 h of treatment, and Western blot analyses demonstrated activation of ER stress markers including CHOP, PERK, and ATF4. In KPL4 xenografts, ERX-41 treatment significantly decreased tumor volume, accompanied by reduced proliferation and increased ER stress marker expression by IHC. Collectively, these findings identify LIPA as a therapeutically actionable vulnerability in IBC and establish ERX-41 as a potential drug for IBC.<\/jats:p>","DOI":"10.3390\/biom16030481","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T13:07:06Z","timestamp":1774271226000},"page":"481","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting LIPA with ERX-41 Induces ER Stress and Inhibits Tumor Progression in Inflammatory Breast Cancer"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-7676-4449","authenticated-orcid":false,"given":"Zenaida","family":"Fuentes","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, 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of Texas Health San Antonio, San Antonio, TX 78229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paulina","family":"Ramirez","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4519-3892","authenticated-orcid":false,"given":"Nicole","family":"Mejia","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chia-Yuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, TX 75080, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott","family":"Elmore","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, TX 75080, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henry","family":"Neal","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, TX 75080, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harika","family":"Nagandla","sequence":"additional","affiliation":[{"name":"Houston Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Panneerdoss","family":"Subbarayalu","sequence":"additional","affiliation":[{"name":"Greehey Children\u2019s Cancer Research Institute, University of Texas Health San Antonio, San Antonio, TX 78229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Uday P.","family":"Pratap","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3003-2954","authenticated-orcid":false,"given":"Christoforos","family":"Thomas","sequence":"additional","affiliation":[{"name":"Houston Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9104-525X","authenticated-orcid":false,"given":"Jung-Mo","family":"Ahn","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, TX 75080, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ganesh V.","family":"Raj","sequence":"additional","affiliation":[{"name":"EtiraRx Inc., Dallas, TX 75247, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7381-6962","authenticated-orcid":false,"given":"Suryavathi","family":"Viswanadhapalli","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA"},{"name":"Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX 78229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2849-4076","authenticated-orcid":false,"given":"Ratna K.","family":"Vadlamudi","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA"},{"name":"Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX 78229, USA"},{"name":"Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, TX 78229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e568","DOI":"10.1016\/S1470-2045(15)00146-1","article-title":"Inflammatory breast cancer: Unique biological and therapeutic considerations","volume":"16","author":"Woodward","year":"2015","journal-title":"Lancet Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1097\/01.cco.0000245307.29026.0a","article-title":"Inflammatory breast cancer: Current understanding","volume":"18","author":"Dirix","year":"2006","journal-title":"Curr. Opin. 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