Endoplasmic reticulum (ER) stress, pyroptosis, and apoptosis are critical molecular events in the occurrence and progress of renal ischemia reperfusion (I/R) injury. Naringenin (4 ′ ,5,7-trihydroxyflavanone) is one of the most widely consumed flavonoids with powerful antioxidant and anti-inflammatory activities. However, whether naringenin is able to relieve renal I/R injury and corresponding mechanisms have not been fully clarified. This study was aimed at exploring its role and relevant mechanisms in renal I/R injury. The C57Bl/6 mice were randomly assigned to receive administration with naringenin (50 mg/kg/d) or sterile saline (1.0 mL/d) for 3 d by gavage and suffered from renal I/R surgery. One specific ER stress inhibitor, 4-phenylbutyric acid (4-PBA, 100 mg/kg/d), was intraperitoneally administered to validate the regulation of ER stress on pyroptosis and apoptosis. Cultured HK-2 cells went through the process of hypoxia/reoxygenation (H/R) to perform cellular experiments with the incubation of naringenin (200 μM), 4-PBA (5 mM), or brusatol (400 nM). The animal results verified that naringenin obviously relieved renal I/R injury, while it refined renal function and attenuated tissue structural damage. Furthermore, naringenin treatment inhibited I/R-induced ER stress as well as pyroptosis and apoptosis as indicated by decreased levels of specific biomarkers such as GRP78, CHOP, caspase-12, NLRP3, ASC, caspase-11, caspase-4, caspase-1, IL-1β, GSDMD-N, BAX, and cleaved caspase-3 in animals and HK-2 cells. Besides, the upregulated expression of Nrf2 and HO-1 proteins after naringenin treatment suggested that naringenin activated the Nrf2/HO-1 signaling pathway, which was again authenticated by the usage of brusatol (Bru), one unique inhibitor of the Nrf2 pathway. Importantly, the application of 4-PBA showed that renal I/R-generated pyroptosis and apoptosis were able to be regulated by ER stress in vivo and in vitro. In conclusion, naringenin suppressed ER stress by activating Nrf2/HO-1 signaling pathway and further alleviated pyroptosis and apoptosis to protect renal against I/R injury.

Clear cell renal cell carcinoma (ccRCC), the major histopathological subtype of renal cancer, is sensitive to ferroptosis. MIT-domain containing protein 1 (MITD1) has been reported to play an important role in hepatocellular carcinoma, while it remains unclear whether MITD1 is involved in ccRCC. Based on available data in The Cancer Genome Atlas, we found the expression of MITD1 increased through bioinformatics analysis and high MITD1 expression suggests a poor prognosis. And we validated that MITD1 expressed significantly in ccRCC through Western blot analysis. Then, we further compared the proliferation and migration capacity of ccRCC before and after MITD1 knockdown and further explored the effect of MITD1 knockdown on ferroptosis. The results indicated that MITD1 knockdown inhibited ccRCC cell proliferation and migration and induced ferroptosis in ccRCC. Furthermore, we found and analyzed the key molecule TAZ which was involved in ferroptosis caused by MITD1 knockdown. Subsequent overexpression experiments demonstrated that MITD1 knockdown induced ferroptosis and suppressed tumor growth and migration through the TAZ/SLC7A11 pathway. In summary, our study revealed the role of MITD1 in the ferroptosis of ccRCC and provided a novel target for ccRCC treatment.

Energy stress is an unfavorable condition that tumor cells are often exposed to. Ferroptosis is considered an emerging target for tumor therapy. However, the role of ferroptosis in energy stress in renal cancer is currently unknown. In this study, we found that glucose deprivation significantly enhanced GPX4-dependent ferroptosis through AMPK activation. Further, AMPK activation suppressed GPX4 expression at the transcriptional level through the upregulation of P53 expression. Additionally, the inactivation of JAK2/STAT3 transcriptionally promoted P53 expression, thereby promoting AMPK-mediated GPX4-dependent ferroptosis. In conclusion, energy stress promotes AMPK-mediated GPX4-dependent erastin-induced ferroptosis in renal cancer through the JAK2/STAT3/P53 signaling axis.

Disulfidptosis is a newly discovered mode of cell death induced by disulfide stress. However, the prognostic value of disulfidptosis-related genes (DRGs) in renal cell carcinoma (RCC) remains to be further elucidated. In this study, consistent cluster analysis was used to classify 571 RCC samples into three DRG-related subtypes based on changes in DRGs expression. Through univariate regression analysis and LASSO-Cox regression analysis of differentially expressed genes (DEGs) among three subtypes, we constructed and validated a DRG risk score to predict the prognosis of patients with RCC, while also identifying three gene subtypes. Analysis of DRG risk score, clinical characteristics, tumor microenvironment (TME), somatic cell mutations, and immunotherapy sensitivity revealed significant correlations between them. A series of studies have shown that MSH3 can be a potential biomarker of RCC, and its low expression is associated with poor prognosis in patients with RCC. Last but not least, overexpression of MSH3 promotes cell death in two RCC cell lines under glucose starvation conditions, indicating that MSH3 is a key gene in the process of cell disulfidptosis. In summary, we identify potential mechanism of RCC progression through DRGs -related tumor microenvironment remodeling. In addition, this study has successfully established a new disulfidptosis-related genes prediction model and discovered a key gene MSH3. They may be new prognostic biomarkers for RCC patients, provide new insights for the treatment of RCC patients, and may inspire new methods for the diagnosis and treatment of RCC patients.

Necroptosis is a type of caspase-independent cell death, and it plays a critical role in regulating the development of cancer. To date, little is known about the role of necroptosis-related genes (NRGs) in clear cell renal cell carcinoma (ccRCC). In this study, we downloaded data regarding the expression of NRGs and overall survival (OS) from The Cancer Genome Atlas (TCGA) database and constructed a risk model to determine the prognostic features of necroptosis using COX regression analysis. Patients with ccRCC were divided into low-risk and high-risk groups based on their risk scores. Thereafter, Kaplan–Meier curves were used to evaluate OS, and receiver operating characteristic (ROC) curves were used to determine the accuracy of prediction. Stratified analyses were performed according to different clinical variables. Furthermore, we assessed the correlation between clinical variables and risk scores; the NRGs with differential expression were mainly enriched in positive regulation of intracellular transport and platinum resistance pathways. We constructed prognostic signatures for OS based on four NRGs and showed that the survival time was significantly longer in the low-risk groups than in the high-risk groups (p < 0.001). The area of the ROC curve for OS was 0.717, indicating excellent predictive accuracy of the established model. Therefore, a predictive model based on NRGs was constructed, which can predict the prognosis of patients and provides insights into the biological mechanisms underlying necroptosis in patients with ccRCC.