Integrated multi-omics analysis reveals NRF2-dependent ferroptosis regulation underlying the renoprotective effects of p-coumaric acid in folic acid-induced AKI.

BACKGROUND: Acute kidney injury (AKI) remains a major clinical challenge lacking effective pharmacological interventions. Ferroptosis has emerged as a critical mechanism contributing to renal tubular injury. While p-coumaric acid (pCA), a natural phenolic compound, has been reported to exert renoprotective effects, its regulatory role in ferroptosis, particularly under different pathological contexts of AKI, remains incompletely understood.

METHODS: A folic acid (FA, 250 mg/kg)-induced AKI model was established in mice treated with pCA (10 and 50 mg/kg). Renal function, histopathology, inflammatory responses, and ferroptosis-related markers were evaluated. Integrated transcriptomic and metabolomic analyses were performed to identify global regulatory alterations. Mechanistic studies were conducted in erastin-treated HK-2 cells. NRF2 signaling involvement was further assessed using pharmacological inhibition.

RESULTS: pCA treatment significantly improved renal function, attenuated tubular injury, and suppressed inflammatory responses in FA-induced AKI. Multi-omics integration revealed that pCA markedly reprogrammed metabolic and transcriptional networks associated with ferroptosis and redox homeostasis. Mechanistically, pCA restored antioxidant capacity and normalized the expression of ferroptosis-related proteins. Notably, pCA activated NRF2 signaling, leading to upregulation of downstream targets involved in ferroptosis regulation. Inhibition of NRF2 partially abolished the cytoprotective and anti-ferroptotic effects of pCA in vitro.

CONCLUSION: pCA alleviates FA-induced AKI by suppressing ferroptosis through NRF2-dependent regulation of redox and metabolic homeostasis, highlighting NRF2 as a potential therapeutic target for AKI.