Abstract
ABSTRACT
Mitochondrial dysfunction drives scleroderma pathogenesis. The mitochondria‐associated 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‐release 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‐β‐induced human dermal fibroblasts (HDFs) and a murine model of LoS. RNA sequencing, molecular docking‐based inverse virtual screening, and surface plasmon resonance (SPR) were used to find possible targets of PTL. Emulsification‐volatilization was used to prepare the PTL‐loaded PLGA nanoparticles. MAM's calcium ion transport function is enhanced, and its quantity increases in LoS. PTL can ameliorate senescence and fibrosis in TGF‐β‐induced HDF cells and the bleomycin‐induced 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‐449 identified as the critical residue for PTL–Ero1L binding. Ero1L overexpression reversed the protective effects of PTL. Additionally, Ero1L knockdown also exhibits anti‐senescence and antifibrotic effects on TGF‐β‐induced HDFs. Furthermore, F127@PLGA@PTL demonstrates excellent sustained‐release properties and significant therapeutic efficacy in the mouse model of LoS. The study demonstrates that PTL alleviates fibrosis of LoS by regulating Ero1L‐mediated MAM stabilization.