Ergothioneine-Associated Transcription Opposes Conserved Mitochondrial Injury Programs in Proximal Tubules

Acute kidney injury (AKI) is characterized by tubular epithelial stress, inflammation, and metabolic dysfunction, yet the transcriptional programs associated with effective metabolic recovery remain poorly defined. Ergothioneine (EGT) has demonstrated renal and mitochondrial protective effects, but its potential involvement in conserved tubular injury programs is unclear. Here, we integrated human and mouse transcriptomic datasets to identify injury-associated programs that were conserved across proximal tubules and oppositely associated with EGT treatment. Pathway-level analyses revealed coordinated inflammatory and redox responses in human AKI, while the mouse intervention model showed broad reversal of disease-associated transcription following EGT treatment. Cross-species analysis of 9700 common orthologs identified seven pathways that consistently exhibited human injury-associated, mouse disease-associated, and EGT-opposed enrichment after removal of cytosolic ribosomal genes. These pathways converged on a mitochondrial bioenergetic–translation program involving oxidative phosphorylation, respiratory electron transport, complex I biogenesis, and mitochondrial translation, together with mTORC1 and MYC signaling. Within this conserved program, OXA1L, NDUFAB1, and TUFM repeatedly contributed to multiple pathway leading edges, highlighting them as potential candidates for functional investigation. Collectively, our findings identify a conserved mitochondrial transcriptional program associated with EGT in injured proximal tubules and provide a mechanistic framework for testing whether modulation of mitochondrial bioenergetics and translation contributes to the renal protective effects of EGT.