Dual PHD2-HDAC inhibitor 31c prevents cisplatin-bevacizumab nephrotoxicity and preserves antitumor efficacy in cervical cancer

Cisplatin-based chemotherapy combined with bevacizumab (CB) remains the standard first-line treatment for advanced or recurrent cervical cancer, integrating cytotoxic and anti-angiogenic mechanisms to improve clinical outcomes. However, treatment success is frequently undermined by dose-dependent nephrotoxicity caused by cisplatin and bevacizumab-induced vascular alterations. Thus, strategies capable of safeguarding renal function without attenuating antitumor activity are urgently needed to optimize treatment durability and patient survival. We previously developed 31c, a novel dual inhibitor of prolyl hydroxylase domain-containing protein 2 (PHD2) and histone deacetylases (HDACs), as a nephroprotective agent. Therefore, we evaluated the nephroprotective potential of 31c in a HeLa xenograft mouse model. Mice were treated with cisplatin, bevacizumab, or their combination, with or without 31c. Tumor growth kinetics and body weight were monitored to assess therapeutic response and systemic toxicity. Renal function was examined through blood urea nitrogen (BUN), serum creatinine (Scr), and erythropoietin (EPO) levels. Kidney tissues underwent histopathological evaluation using hematoxylin and eosin (H&E) and Masson's trichrome staining to quantify tubular injury and fibrosis. RNA sequencing (RNA-seq) of kidney samples identified transcriptomic alterations, and immunofluorescence staining validated renal injury markers lipocalin-2 (Lcn2/NGAL) and kidney injury molecule-1 (Havcr1/KIM-1). Co-administration with 31c preserved the antitumor efficacy of the CB regimen, yielding tumor inhibition comparable to CB alone. Notably, 31c markedly reduced renal toxicity. Mice receiving CB alone displayed significant increases in BUN and Scr levels, extensive tubular degeneration, and marked collagen accumulation, hallmarks of acute renal injury and fibrosis. In contrast, 31c significantly reduced these pathological changes and maintained normal tubular structure. Transcriptomic profiling revealed distinct clustering among treatment groups, with 31c partially reversing CB-induced transcriptional dysregulation. Among the most upregulated genes in CB group, Lcn2 and Havcr1 were significantly suppressed by31c, consistent with immunofluorescence validation. The dual PHD2-HDAC inhibitor 31c confers robust nephroprotection against cisplatin-bevacizumab-induced renal injury without compromising antitumor activity. This integrated protective strategy highlights a promising approach to enhance the safety, tolerability, and continuity of platinum-anti-angiogenic therapies. By preserving renal integrity, 31c may support sustained treatment intensity and prolonged therapeutic benefit in patients with advanced cervical cancer and potentially other malignancies treated with similar regimens.