Renal tubule-targeted dexrazoxane suppresses ferroptosis in acute kidney injury by inhibiting ACMSD

Acute kidney injury(AKI)is a heterogeneous clinical complication with no existing definite or particular therapies.Therefore,molecular mechanisms and approaches for treating acute kidney injury are in urgent need.Herein,we demonstrated that dexrazoxane(DXZ),a U.S.Food and Drug Administration(FDA)-approved cardioprotective drug,can both functionally and histologically attenuate cisplatin or ischemia-reperfusion injury-induced AKI in vitro and in vivo via inhibiting ferroptosis specifically.This effect is characterized by decreasing lipid peroxidation,shown by the biomarker of oxidative stress 4-hydroxynonenal(HNE)and prostaglandinendoperoxide synthase 2(Ptgs2),while reversing the downregulation of glutathione peroxidase 4(GPX4)and ferritin 1(FTH-1).Mechanistically,the results revealed that DXZ targeted at the renal tubule significantly inhibits ferroptosis by suppressingα-amino-β-carboxymuconate-ε-semialdehyde decarboxylase(ACMSD).Furthermore,the conjugation of dexrazoxane and polysialic acid(DXZ-PSA)is specifically designed and utilized to enhance the therapeutic effect of DXZ by long-term effect in the kidney,especially retention and targeting in the renal tubules.This study provides a novel therapeutic approach and mechanistic insight for AKI by inhibiting ferroptosis through a new type drug DXZPSA with the enhanced renal distribution.

LncFASA promotes cancer ferroptosis via modulating PRDX1 phase separation

Ferroptosis, a unique type of non-apoptotic cell death resulting from iron-dependent lipid peroxidation, has a potential physiological function in tumor suppression, but its underlying mechanisms have not been fully elucidated. Here, we report that the long non-coding RNA(lncRNA) LncFASA increases the susceptibility of triple-negative breast cancer(TNBC) to ferroptosis. As a tumor suppressor, LncFASA drives the formation of droplets containing peroxiredoxin1(PRDX1), a member of the peroxidase family, resulting in the accumulation of lipid peroxidation via the SLC7A11-GPX4 axis. Mechanistically, LncFASA directly binds to the Ahpc-TSA domain of PRDX1, inhibiting its peroxidase activity by driving liquid-liquid phase separation, which disrupts intracellular ROS homeostasis. Notably, high LncFASA expression indicates favorable overall survival in individuals with breast cancer, and LncFASA impairs the growth of breast xenograft tumors by modulating ferroptosis. Together, our findings illustrate the crucial role of this lncRNA in ferroptosis-mediated cancer development and provide new insights into therapeutic strategies for breast cancer.

Targeting iron metabolism using gallium nanoparticles to suppress ferroptosis and effectively mitigate acute kidney injury

Ferroptosis plays a critical pathophysiological role in several types of acute kidney injury(AKI).The development of nanomaterials targeting iron metabolism and ferroptosis is a promising approach for AKI treatment.Herein,we synthesized gallic acid-gallium polyvinyl pyrrolidone nanoparticles(GGP NPs)as a potential iron-scavenging agent because of their nearly ionic radius and chemical similarity with iron.The results indicated that GGP NPs accumulated in tubular epithelial cells and showed good biocompatibility.GGP NPs significantly inhibited cisplatin(CP)-induced ferroptosis in HK-2 cells by reducing the accumulation of intracellular free iron and mitochondrial dysfunction,and suppressing the perturbations of ferroptosis processes,including lipid peroxidation,nicotinamide adenine dinucleotide phosphate(NADPH)and glutathione(GSH)levels,glutathione peroxidase 4(GPX4)activity,and ferritinophagy.An in vivo study demonstrated that treatment with GGP NPs significantly ameliorated the renal tubular injury and mitochondrial damage induced by CP treatment or ischemia-reperfusion injury.Our study suggests that GGP NPs may be an effective and promising candidate for AKI treatment and enable potential clinical translation.