Chemotherapy-induced renal ischemia-reperfusion injury and its psychosocial consequences in oncology patients: mechanistic evidence from the Nrf2/HO-1/NQO1–mitophagy pathway and implications for multidisciplinary cancer care

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Background: Chemotherapy-induced renal ischemia-reperfusion injury (CI-RIRI) is an undercharacterized but clinically significant complication in oncology, impacting an estimated 30-45% of patients undergoing platinum-based and antiangiogenic therapy. The molecular interaction between oxidative stress, dysregulation of mitophagy and the Nrf2/HO-1/NQO1 cytoprotective axis has not been fully studied in the framework of its subsequent psychosocial consequences. Objective: The study was conducted to (1) clarify the mechanistic role of Nrf2/HO-1/ NQO1 -PINK1 -Parkin mitophagy pathway in CI-RIRI, (2) measure the renal functional decline during multiple chemotherapy cycles, (3) determine the psychosocial burden in patients with CI-RIRI, and (4) recommend evidence-based multidisciplinary care frameworks. Methods: A potential observational cohort study recruited 284 adult oncology patients receiving cisplatin, oxaliplatin, carboplatin, or bevacizumab regimens in three tertiary centers (2022-2024). Renal biomarkers (serum creatinine, cystatin C, NGAL, KIM-1, IL-18), Nrf2 pathway proteins (HO-1, NQO1, Keap1), mitophagy markers (PINK1, Parkin, LC3B-II, p62), and psychosocial instruments (PHQ-9, GAD-7, FACT-G, renal-specific QoL) were assessed at baseline, mid-treatment (cycle 3), and post-treatment (cycle 6). Results: CI-RIRI was detected among 38.4% of patients (n=109). Significant suppression of Nrf2 nuclear translocation (mean fold-change: −2.8±0.6, p<0.001) and HO-1 expression (−3.1±0.7, p<0.001) coincided with mitophagy impairment (elevated p62: +4.2±1.1, p<0.001) and elevated urinary NGAL (mean 187.4±42.3 ng/mL vs. 28.6±8.1 ng/mL in controls, p<0.001). Patients with CI-RIRI exhibited significantly higher rates of depression (PHQ-9 ≥10: 54.1% vs. 23.7%, p<0.001), anxiety (GAD-7 ≥10: 49.5% vs. 19.8%, p<0.001), and markedly reduced FACT-G total scores (78.4±14.2 vs. 101.3±12.6, p<0.001). Multivariate logistic regression revealed that Nrf2 down-regulation (OR 4.72, 95%CI 2.83-7.87), cisplatin cumulative dose above 400 mg/m2 (OR 3.91, 95%CI 2.14-7.13) and baseline anxiety (OR 2.47, 95%CI 1.38–4.42) as independent predictors of moderate-to-severe CI-RIRI. Conclusion: CI-RIRI is mechanistically mediated by Nrf2/HO-1/NQO1 pathway repression and mitophagy failure, and has severe and reciprocal psychosocial impacts. The combination of nephroprotective pharmacological approaches on the Nrf2 axis and the organization of psychosocial interventions in multidisciplinary oncology care is a pressing need.

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