Necroptosis refers to a regulated form of cell death induced by a variety of stimuli. Although it has been implicated in the pathogenesis of many diseases, there is evidence to support that necroptosis is not purely a detrimental process. We propose that necroptosis is a “double-edged sword” in terms of physiology and pathology. On the one hand, necroptosis can trigger an uncontrolled inflammatory cascade response, resulting in severe tissue injury, disease chronicity, and even tumor progression. On the other hand, necroptosis functions as a host defense mechanism, exerting antipathogenic and antitumor effects through its powerful pro-inflammatory properties. Moreover, necroptosis plays an important role during both development and regeneration. Misestimation of the multifaceted features of necroptosis may influence the development of therapeutic approaches targeting necroptosis. In this review, we summarize current knowledge of the pathways involved in necroptosis as well as five important steps that determine its occurrence. The dual role of necroptosis in a variety of physiological and pathological conditions is also highlighted. Future studies and the development of therapeutic strategies targeting necroptosis should fully consider the complicated properties of this type of regulated cell death.

Homogeneity and heterogeneity of the cytopathological mechanisms in different etiology-induced acute kidney injury (AKI) are poorly understood. Here, we performed single-cell sequencing (scRNA) on mouse kidneys with five common AKI etiologies (CP-Cisplatin, IRI-Ischemia-reperfusion injury, UUO-Unilateral ureteral obstruction, FA-Folic acid, and SO-Sodium oxalate). We constructed a potent multi-model AKI scRNA atlas containing 20 celltypes with 80,689 high-quality cells. The data suggest that compared to IRI and CP-AKI, FA- and SO-AKI exhibit injury characteristics more similar to UUO-AKI, which may due to tiny crystal-induced intrarenal obstruction. Through scRNA atlas, 7 different functional proximal tubular cell (PTC) subtypes were identified, we found that Maladaptive PTCs and classical Havcr1 PTCs but not novel Krt20 PTCs affect the pro-inflammatory and pro-fibrotic levels in different AKI models. And cell death and cytoskeletal remodeling events are widespread patterns of injury in PTCs. Moreover, we found that programmed cell death predominated in PTCs, whereas apoptosis and autophagy prevailed in the remaining renal tubules. We also identified S100a6 as a novel AKI-endothelial injury biomarker. Furthermore, we revealed that the dynamic and active immune (especially Arg1 Macro_2 cells) -parenchymal cell interactions are important features of AKI. Taken together, our study provides a potent resource for understanding the pathogenesis of AKI and early intervention in AKI progression at single-cell resolution.

The IDH1-R132H mutation is implicated in the development of various tumors. Whether cisplatin, a common chemotherapeutic agent, induces more significant renal toxicity in individuals with the IDH1-R132H mutation remains unclear. In this study, we observed that the IDH1-R132H mutation exacerbates mitochondrial lipid peroxidation and dysfunction in renal tubules, rendering the kidneys more susceptible to cisplatin-induced ferroptosis. The IDH1-R132H mutation increases methylation of the Ndufa1 promoter, thereby suppressing NDUFA1 transcription and translation. This suppression disrupts NDUFA1’s interaction with FSP1, reducing its resistance to cisplatin-induced tubular epithelial cell death. As a consequence, ROS accumulates, lipid peroxidation occurs, and ferroptosis is triggered, thereby promoting acute kidney injury. In summary, this study elucidates a novel mechanism underlying cisplatin-induced nephrotoxicity and provides valuable insights for the development of personalized treatment strategies for tumor patients carrying the IDH1-R132H mutation.

Key Points: Gene deletions of Zbp1, Ripk3, and Mlkl reduced severity of oxalate-induced AKI. Mice with mutation or deletion in the Z-nucleic acid sensing domain (Zα) of Z-DNA binding protein 1 were protected from AKI. Z-DNA binding protein 1 sensed mitochondrial Z-DNA through its Zα domain, recruited receptor-interacting protein kinase 3 through receptor-interacting protein homotypic interaction motif, and activated mixed lineage kinase domain-like to induce necroptosis. Background: Calcium oxalate–induced acute kidney injury is a severe condition in which the kidneys suffer rapid damage due to the deposition of oxalate crystals. Known factors contributing to cell death induced by calcium oxalate include receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) protein–dependent necroptosis, as well as necrosis involving peptidylprolyl isomerase F–mediated mitochondrial permeability transition. However, the detailed molecular mechanisms linking mitochondrial dysfunction to RIPK3 activation are not fully understood. Methods: Mice with gene knockout of Zbp1, Ripk3, or Mlkl and mice with mutations in the Z-nucleic acid sensing domain of Z-DNA binding protein 1 (ZBP1) or deletion of Zα1 were used in an oxalate-induced AKI model. Proximal renal tubule cells were isolated and cultured for further investigation. Human oxalate nephropathy biopsy samples were analyzed. Results: Specific gene deletions of Zbp1, Ripk3, or Mlkl in proximal renal tubules significantly reduced the severity of oxalate-induced AKI by preventing necroptosis and subsequent inflammation. Notably, mice with mutations in the Z-nucleic acid sensing domain of ZBP1 or deletion of Zα1 were protected from AKI. In cultured proximal tubular cells, calcium oxalate damaged mitochondria, accompanied by an increase in Bax and a decrease in BCL2 and transcription factor A, mitochondrial (TFAM), leading to the release of mitochondrial Z-DNA. ZBP1 sensed this mitochondrial Z-DNA and then recruited RIPK3 through the receptor-interacting protein homotypic interaction motifs, which in turn activated MLKL through RIPK3 phosphorylation, leading to necroptosis and contributing to AKI. Conclusions: ZBP1 plays a critical role in sensing mitochondrial Z-DNA and initiating RIPK3/MLKL-mediated necroptosis, contributing to the development of oxalate-induced AKI.

Background: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease that may lead to end-stage renal disease. However, few specifific biomarkers are available for AAV-related renal injury. The aim of this study was to identify important biomarkers and explore new immune subtypes of AAV-related renal injury.Methods: In this study, messenger RNA expression profiles for antibody-associated vasculitis and AAV-associated kidney injury were downloaded from the Gene Expression Omnibus database. Weighted gene co-expression network analysis (WGCNA) was performed to identify the most relevant module genes to AAV. Key module genes from WGCNA were then intersected with AAV- and nephropathy-related genes from the Genecards database to identify key genes for AAV-associated kidney injury. Subsequently, the expression of key genes was validated in independent datasets and the correlation of genes with clinical traits of kidney injury was verified by the Nephroseq database. Finally, non-negative matrix factorization (NMF) clustering was performed to identify the immune subtypes associated with the key genes.Results: Eight co-key genes (AGTR2, ANPTL2, BDKRB1, CSF2, FGA, IL1RAPL2, PCDH11Y, and PGR) were identifified, and validated the expression levels independent datasets. Receiver operating characteristic curve analysis revealed that these eight genes have major diagnostic value as potential biomarkers of AAV-related renal injury. Through our comprehensive gene enrichment analyses, we found that they are associated with immune-related pathways. NMF clustering of key genes identified two and three immune-related molecular subtypes in the glomerular and tubular data, respectively. A correlation analysis with prognostic data from the Nephroseq database indicated that the expression of co-key genes was positively co-related with the glomerular filtration rate.Discussion: Altogether, we identifified 8 valuable biomarkers that firmly correlate with the diagnosis and prognosis of AAV-related renal injury. These markers may help identify new immune subtypes for AAV-related renal injury.