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.