Overexpression of myo-inositol oxygenase (MIOX), a proximal tubular enzyme, exacerbates cellular redox injury in acute kidney injury (AKI). Ferroptosis, a newly coined term associated with lipid hydroperoxidation, plays a critical role in the pathogenesis of AKI. Whether or not MIOX exacerbates tubular damage by accelerating ferroptosis in Cisplatin-induced AKI remains elusive. Cisplatin-treated HK-2 cells exhibited notable cell death, which was reduced by ferroptosis inhibitors. Also, alterations in various ferroptosis metabolic sensors, including lipid hydroperoxidation, glutathione peroxidase 4 (GPX4) activity, NADPH and reduced glutathione (GSH) levels, and ferritinophagy, were observed. These perturbations were accentuated by MIOX overexpression, while ameliorated by MIOX knockdown. Likewise, Cisplatin-treated CD1 mice exhibited tubular damage and derangement of renal physiological parameters, which was alleviated by Ferrostatin-1 (Fer-1), a ferroptosis inhibitor. To investigate the relevance of MIOX to ferroptosis, Wild-type (WT) mice, MIOX-overexpressing transgenic (MIOX-TG) mice and MIOX knockout (MIOX-KO) mice were subjected to Cisplatin treatment. In comparison to Cisplatin-treated WT mice, Cisplatin-treated MIOX-TG mice had more severe renal pathological changes and perturbations in ferroptosis metabolic sensors, which were minimal in Cisplatin-treated MIOX-KO mice. In conclusion, these findings indicate that ferroptosis, an integral process in the pathogenesis of Cisplatin-induced AKI, is modulated by the expression profile of MIOX.

Regulated cell death (RCD), distinct from accidental cell death, refers to a process of well-controlled programmed cell death with well-defined pathological mechanisms. In the past few decades, various terms for RCDs were coined, and some of them have been implicated in the pathogenesis of various types of acute kidney injury (AKI). Cisplatin is widely used as a chemotherapeutic drug for a broad spectrum of cancers, but its usage was hampered because of being highly nephrotoxic. Cisplatin-induced AKI is commonly seen clinically, and it also serves as a well-established prototypic model for laboratory investigations relevant to acute nephropathy affecting especially the tubular compartment. Literature reports over a period of three decades have indicated that there are multiple types of RCDs, including apoptosis, necroptosis, pyroptosis, ferroptosis, and mitochondrial permeability transition-mediated necrosis, and some of them are pertinent to the pathogenesis of cisplatin-induced AKI. Interestingly, myo-inositol metabolism, a vital biological process that is largely restricted to the kidney, seems to be relevant to the pathogenesis of certain forms of RCDs. A comprehensive understanding of RCDs in cisplatin-induced AKI and their relevance to myo-inositol homeostasis may yield novel therapeutic targets for the amelioration of cisplatin-related nephropathy.

Cisplatin is one of the major causes of acute kidney injury (AKI) in clinical practice, and ferroptosis is an essential form of cell death in cisplatin-induced AKI (CP-AKI). WW domain binding protein-2 (WBP2), a molecular chaperon, is involved in the progression of various malignancies, but its role in renal injuries has not been investigated. Our present study employed bioinformatics analysis to identify WBP2 as a potential modulator of AKI and ferroptosis. Preliminary laboratory investigations showed that WBP2, highly expressed in renal proximal tubular cells, was downregulated in CP-AKI. Further studies demonstrated that WBP2 decelerated ferroptosis to alleviate CP-AKI. Mechanistically, WBP2 interacted with glutathione peroxidase 4 (GPX4, a key detoxicating enzyme for ferroptosis) via its PPXY1 motif to inhibit ferroptosis. Furthermore, the in-depth investigations revealed that WBP2 competed with heat shock cognate protein 70 (HSC70) for the binding with the KEFRQ-like motifs of GPX4, leading to the deceleration of chaperon-mediated autophagy of GPX4. All in all, this study indicated the beneficial effect of WBP2 in CP-AKI and its relevance with ferroptosis, thus providing a novel insight into the modulation of ferroptosis in cisplatin-related nephropathy.

Ferroptosis, an iron‐dependent cell death pathway driven by lipid peroxidation, has emerged as a critical pathophysiological mechanism linking cancer and inflammatory diseases. The seemingly distinct pathologies exhibit shared microenvironmental hallmarks—oxidative stress, immune dysregulation, and metabolic reprogramming—that converge on ferroptosis regulation. This review synthesizes how ferroptosis operates at the intersection of these diseases, acting as both a tumor‐suppressive mechanism and a driver of inflammatory tissue damage. In cancer, ferroptosis eliminates therapy‐resistant cells but paradoxically facilitates metastasis through lipid peroxidation byproducts that remodel the tumor microenvironment and suppress antitumor immunity. In chronic inflammatory diseases—from atherosclerosis to rheumatoid arthritis—ferroptosis amplifies neuroinflammatory cascades while simultaneously exposing vulnerabilities for therapeutic targeting. Central to this duality are shared regulatory nodes, including nuclear factor kappa B‐driven inflammation, NOD‐like receptor family pyrin domain‐containing 3 inflammasome activation, and GPX4 dysfunction. Therapeutically, ferroptosis induction shows promise against therapy‐resistant cancers but risks exacerbating inflammatory damage, underscoring the need for precision modulation. Emerging strategies—nanoparticle‐based inducers, immunotherapy combinations, and biomarker‐guided patient stratification—aim to balance prodeath efficacy against off‐target toxicity. By dissecting the ferroptosis–inflammation–cancer axis, this review provides a unified framework for understanding disease pathogenesis and advancing therapies for conditions resistant to conventional treatments. Future research must prioritize spatial mapping of ferroptosis dynamics, mechanistic crosstalk with immune checkpoints, and combinatorial regimens that exploit ferroptosis vulnerabilities while mitigating its inflammatory consequences.

Myo-inositol, a carbocyclic sugar, is believed to be relevant to renal pathobiology since the kidney is the major site for its catabolism. Its role in acute kidney injury (AKI) has not been fully investigated. Ferroptosis, a unique form of regulated cell death, is involved in various types of renal injuries. The relevance of myo-inositol with respect to the process of ferroptosis has not been explored either. Herein, our current exploratory studies revealed that supplementation of myo-inositol attenuates cisplatin-induced injury in cultured Boston University mouse proximal tubular (BUMPT) cells and renal tubules in vivo. Moreover, our studies unraveled that metabolic parameters pertaining to ferroptosis were disrupted in cisplatin-treated proximal tubular cells, which were seemingly remedied by the administration of myo-inositol. Mechanistically, we noted that cisplatin treatment led to the up-regulation of NOX4, a key enzyme relevant to ferroptosis, which was normalized by the administration of myo-inositol. Furthermore, we observed that changes in the NOX4 expression induced by cisplatin or myo-inositol were modulated by carboxy-terminus of Hsc70-interacting protein (CHIP), an E3 ubiquitin ligase. Taken together, our investigation suggests that myo-inositol promotes CHIP-mediated ubiquitination of NOX4 to decelerate the process of ferroptosis, leading to the amelioration of cisplatin-induced AKI.