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The mitochondria\u2010associated endoplasmic reticulum membrane (MAM) regulates mitochondrial function. Parthenolide (PTL) has protective effects on mitochondria. However, its specific role and mechanisms in localized scleroderma (LoS) remain unclear. This study investigates whether PTL reduces senescence and skin fibrosis by stabilizing MAM in LoS and examines the protective effects of a synthesized thermosensitive controlled\u2010release hydrogel (F127@PLGA@PTL) against LoS. We employed transmission electron microscopy (TEM) to observe MAM abnormalities in LoS skin lesions. Other multiple molecular biology experiments were conducted to investigate how PTL protects against LoS in TGF\u2010\u03b2\u2010induced human dermal fibroblasts (HDFs) and a murine model of LoS. RNA sequencing, molecular docking\u2010based inverse virtual screening, and surface plasmon resonance (SPR) were used to find possible targets of PTL. Emulsification\u2010volatilization was used to prepare the PTL\u2010loaded PLGA nanoparticles. MAM's calcium ion transport function is enhanced, and its quantity increases in LoS. PTL can ameliorate senescence and fibrosis in TGF\u2010\u03b2\u2010induced HDF cells and the bleomycin\u2010induced LoS model by regulating the IP3R1\/Grp75\/VDAC1 complex and repairing mitochondrial damage. Notably, mechanistically, this protective effect was mediated through Ero1L suppression, with ARG\u2010449 identified as the critical residue for PTL\u2013Ero1L binding. Ero1L overexpression reversed the protective effects of PTL. Additionally, Ero1L knockdown also exhibits anti\u2010senescence and antifibrotic effects on TGF\u2010\u03b2\u2010induced HDFs. Furthermore, F127@PLGA@PTL demonstrates excellent sustained\u2010release properties and significant therapeutic efficacy in the mouse model of LoS. The study demonstrates that PTL alleviates fibrosis of LoS by regulating Ero1L\u2010mediated MAM stabilization.<\/jats:p>","DOI":"10.1111\/acel.70738","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:57:31Z","timestamp":1790744251000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting\n                    <scp>Ero1L<\/scp>\n                    by Parthenolide Alleviates Cellular Senescence and Fibrosis of Localized Scleroderma by Regulating Mitochondria\u2010Associated Endoplasmic Reticulum Membranes Stabilization"],"prefix":"10.1111","volume":"25","author":[{"given":"Fei","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Dermatology West China Hospital, Sichuan University  Chengdu China"},{"name":"Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease\u2010Related Molecular Network, West China Hospital Sichuan University  Chengdu China"},{"name":"Department of Dermatology Lanzhou University Second Hospital  Lanzhou China"},{"name":"The Second Clinical Medical School Lanzhou University  Lanzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ru","family":"Xing","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences Harbin Medical University  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meijuan","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Dermatology West China Hospital, Sichuan University  Chengdu China"},{"name":"Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease\u2010Related Molecular Network, West China Hospital Sichuan University  Chengdu 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Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4224-0718","authenticated-orcid":false,"given":"Xiaoyan","family":"Lyu","sequence":"additional","affiliation":[{"name":"Department of Dermatology West China Hospital, Sichuan University  Chengdu China"},{"name":"Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease\u2010Related Molecular Network, West China Hospital Sichuan University  Chengdu 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