Allergy · 2025
Targeting the Galectin-7/TRPM2/Zn2+/DRP-1 Signaling Pathway: A Potential Therapeutic Intervention in the Pathogenesis of SJS/TEN.
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Zhang Chen, Pang BingYu, Luo YiXin, Cao Zipeng, Qiao Pei, Zhu ZhenLai, Fang Hui, Yang JianKang, Dang ErLe, Shen ShengXian, Kang Pan, Jiao Qingqing, Hasegawa Akito, Abe Riichiro, Qiao HongJiang, Wang Gang, Fu Meng
Аннотация
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: Targeting the galectin-7/TRPM2/Zn2+/DRP-1 signaling pathway in keratinocytes presents a prospective therapeutic strategy for mitigating SJS/TEN in the future.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: Targeting the galectin-7/TRPM2/Zn2+/DRP-1 signaling pathway in keratinocytes presents a prospective therapeutic strategy for mitigating SJS/TEN in the future.