Targeting the Galectin-7/TRPM2/Zn²⁺/DRP-1 Signaling Pathway: A Potential Therapeutic Intervention in the Pathogenesis of SJS/TEN.

Abstract

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) represent a spectrum of severe drug-induced cutaneous reactions. These conditions are characterized by widespread and confluent keratinocyte apoptosis, which differentiates them from erythema multiforme (EM). Mounting evidence has implicated the mitochondrial-dependent apoptosis pathway in the pathogenesis of SJS/TEN, but the potential roles and specific mechanisms of these pathways in SJS/TEN remain largely unexplored. Proteomic analyses were conducted to investigate differential protein expression in blister fluid (BF)-derived exosomes from suction surgery in healthy individuals (Con Exo) or patients with EM (EM Exo) or SJS/TEN (TEN Exo). Further analysis involved glutathione S-transferase (GST) pull-down assay, liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, and validation of MS results through proximity ligation assay (PLA) and coimmunoprecipitation (co-IP). Phenotypic and mechanistic analyses were performed using immunohistochemistry (IHC) staining, enzyme-linked immunosorbent assay (ELISA), western blotting, reverse transcription-polymerase chain reaction (RT-PCR), co-IP, CCK-8 assay, adenosine triphosphate (ATP) level measurements, and flow cytometry. Galectin-7 was markedly upregulated in BF-derived exosomes from SJS/TEN patients and showed a correlation with disease severity. Further analysis confirmed the interaction between galectin-7 and transient receptor potential (melastatin) 2 (TRPM2). BF-derived exosomes from SJS/TEN patients induced an imbalance in mitochondrial dynamics via galectin-7/TRPM2 upregulation. Activation of TRPM2 led to an elevation in mitochondrial Zn²⁺, which facilitated the recruitment of the fission factor dynamin-related protein-1 (DRP-1) to mitochondria to trigger mitochondrial fission in the keratinocyte. In addition, the recruitment of DRP-1-dependent mitochondrial fission via the voltage-dependent anion channel 1 (VDAC1)/hexokinase 2 (HK2)-mediated opening of the mitochondrial permeability transition pore (mPTP)-triggered cytochrome c release. These effects ultimately induce activation of the intrinsic mitochondrial apoptotic pathway and contribute to the pathogenesis of SJS/TEN. Targeting the galectin-7/TRPM2/Zn²⁺/DRP-1 signaling pathway in keratinocytes presents a prospective therapeutic strategy for mitigating SJS/TEN in the future.