PRDX1 as a Redox Gatekeeper at Mitochondrial-ER Contact Sites: Implications for Kidney Fibrosis Progression and Therapy

Peroxiredoxins (PRDXs) constitute a class of thiol-dependent oxidoreductive regulatory factors whose functions extend beyond peroxide detoxification to include the regulation of oxidoreductive signaling, organelle homeostasis, and cell fate determination. The emerging role of PRDX1-6 in fibrotic diseases-particularly PRDX1's function as an oxidoreductive signaling modulator dependent on specific pathological contexts during renal injury and fibrosis-calls for further investigation. We propose a dual-regulatory model in which PRDX1 simultaneously governs both the mitochondrial reactive oxygen species (ROS)-JNK/Smad signaling pathway and the endoplasmic reticulum (ER) stress-protein kinase R-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2α (eIF2α)/activating transcription factor 4 (ATF4)/C/EBP homologous protein (CHOP)-gasdermin E (GSDME) signaling pathway, thereby linking organelle oxidoreductive imbalance to epithelial cell injury, inflammatory cell death, and fibrotic remodeling. Notably, we hypothesize that the mitochondria-associated membranes (MAMs) serve as a critical spatial interface for the convergence of these signaling pathways. At the MAMs, PRDX1 may function as an "oxidoreductive gatekeeper," buffering local peroxide signaling while coordinating the oxidoreductive balance, Ca2+ transport, and mitochondrial homeostasis between the ER and mitochondria. This theoretical framework provides a potential basis for elucidating the context-dependent role of PRDX1 in both acute and chronic renal injury, and identifies the PRDX1-MAMs oxidoreductive gating axis as a promising therapeutic target for renal fibrosis.