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CircRNA GRAMD4 induces NBR1 expression to promote autophagy and immune escape in renal cell carcinoma

Mi Zhou,Minyu Chen,Zhousan Zheng,Qihao Li,Lican Liao,Yunfei Wang,Yi Xu,Guannan Shu,Junhang Luo,Taowei Yang,Jiaxing Zhang

The tumor microenvironment (TME) in renal cell carcinoma (RCC) frequently exhibits significant immune cell infiltration. However, tumor cells often manage to evade immune surveillance. This study revealed the mechanism by which circular RNA circGRAMD4 regulates NBR1. CircGRAMD4 is markedly elevated in RCC, and its high levels are correlated with a poor prognosis. Notably, the absence of circGRAMD4 has been demonstrated to result in a significant inhibition of renal cancer cell growth. This inhibition has been attributed to an enhanced anti-tumor immunity mediated by CD8+ T cells. Mechanistically, circGRAMD4 interacts with the RBM4 protein, stabilizing the autophagic cargo receptor NBR1 mRNA. This interaction promotes NBR1 expression, which in turn leads to the degradation of MHC-I molecules through macroautophagy/autophagy pathways. Consequently, this process affects renal cancer cell antigen presentation, induces CD8+ T cell dysfunction, and contributes to tumor immune escape. Moreover, by inhibiting circGRAMD4 and using immune checkpoint blockers (ICB), the immunosuppressive TME is altered to prevent tumor immune evasion, ultimately increasing the effectiveness of ICB treatment. The discovery highlights the significant impact of circGRAMD4 on RCC immune escape and proposes that blocking circGRAMD4 could serve as a promising immunotherapy strategy when combined with ICB to enhance patient outcomes.

Fusobacterium nucleatum and its metabolite hydrogen sulfide alter gut microbiota composition and autophagy process and promote colorectal cancer progression

Minyu Wang,Zheng Wang,Duncan James Lessing,Min Guo,Weihua Chu

Fusobacterium nucleatum is a harmful bacterium that produces hydrogen sulfide by metabolizing sulfur-containing amino acids, both of which have been shown to promote/initiate the development of various cancers, such as colorectal cancer, liver cancer, as well as lung cancer. However, few studies have reported how F. nucleatum acts on gut microbiota, influences the autophagy process, and promotes the development of colorectal cancer through the metabolite hydrogen sulfide. It was found that HCT116 cells secreted more inflammatory factors and showed higher survival as well as migration rate when given a pathological concentration of hydrogen sulfide. Using cellular transcriptome sequencing, it could be seen that after giving HCT116 cells F. nucleatum or F. nucleatum with L-cysteine, many inflammation-related signaling pathways, including autophagic pathways, were elevated compared to the control group. In vivo, the mice in the model groups displayed cancer progression, and the expression of some of the autophagy-related genes, DRAM1, NBR1, ATG7, MAP1LC3A were also increased in mice given F. nucleatum or F. nucleatum with L-cysteine when compared to the untreated control mice. The number of certain probiotic bacteria and fungi in the mice given F. nucleatum or F. nucleatum and L-cysteine decreased significantly; in contrast, the number of potentially pathogenic bacteria and fungi increased. These findings suggest that F. nucleatum and its metabolite hydrogen sulfide can modulate intestinal microbiota and autophagy as well as promote the development and progression of colorectal cancer.

NBR1-mediated autophagic degradation of YTHDF1 curtails FDX1 translation to drive concurrent multikinase inhibitor resistance and cuproptosis tolerance

Weikai Wang,Xin Jiang,Xiaona Chen,Kaiyu Liang,Miaoqin Chen,Kaizhong Lu,Qi Wei,Yuchen Wu,Liyuan Zhu,Yuan Chen,Tianlun Hou,Jingfeng Luo,Chentao Li,Xian Wang,Hongchuan Jin,Lifeng Feng

NBR1-Regulated Mitochondrial Quality Control in Sertoli Cells Is Involved in the Male Reproductive Damage Induced by Chronic Diquat Poisoning, Which Is Ameliorated by Spermidine

Po Gao,Bingyu Ling,Jiaheng Lin,Qiong Du,Zengzhen Wei,Bowen Fan,Zhenhao Jiang,Xiaolong Wu,Ning Bu,Qiaoqiao Zhou,Jialin Qin,Jinsong Zhang

Diquat (DQ) is a widely used herbicide, whose residues have been detected in food products, raising concerns about potential health risks. Nevertheless, the mechanisms underlying male reproductive damage after chronic DQ exposure remain unclear. In this study, we observed that chronic DQ exposure reduces Sertoli cell numbers and triggers mitochondrial quality control (MQC) impairment, oxidative stress, apoptosis, and blood–testis barrier (BTB) disruption in testicular tissue. Mechanistically, DQ downregulates NBR1 in Sertoli cells, leading to impaired mitophagy flux, increased mitochondrial fission, and elevated oxidative stress, which ultimately promote Sertoli cell apoptosis and compromise cellular barrier function. Metabolomic analysis indicated that chronic DQ exposure lowers spermidine (SPD) levels in the mouse testes. Exogenous SPD supplementation attenuated DQ-induced MQC dysfunction, oxidative stress, apoptosis, and BTB damage. Together, these results establish NBR1 as a critical regulator of DQ-triggered Sertoli cell injury and propose SPD as a potential therapeutic candidate for alleviating DQ-induced male reproductive impairment.