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

Abstract

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.

Key Findings

• p-coumaric acid (pCA) treatment significantly improved renal function and attenuated tubular injury in folic acid-induced acute kidney injury (AKI).
• Multi-omics analysis revealed that pCA reprogrammed metabolic and transcriptional networks related to ferroptosis and redox homeostasis.
• pCA activated NRF2 signaling, which upregulated downstream targets involved in ferroptosis regulation, and inhibition of NRF2 partially abolished pCA's protective effects.

Clinical Significance

Citation

Ma Hongchuang, Shen Nan, Liu Xinet al.. Integrated multi-omics analysis reveals NRF2-dependent ferroptosis regulation underlying the renoprotective effects of p-coumaric acid in folic acid-induced AKI. Chemico-biological interactions. 2026-Jul-25.