Clear cell renal cell carcinoma (ccRCC) is one of the most prevalent cancers, and PANoptosis is a distinct, inflammatory-programmed cell death regulated by the PANoptosome. The essential regulators of cancer occurrence and progression are microRNAs (miRNAs). However, the potential function of PANoptosis-related microRNAs (PRMs) in ccRCC remains obscure. This study retrieved ccRCC samples from The Cancer Genome Atlas database and three Gene Expression Omnibus datasets. PRMs were recognized based on previous reports in the scientific literature. Regression analyses were used to identify the prognosis PRMs and construct a PANoptosis-related miRNA prognostic signature based on the risk score. We discovered that high-risk patients had poorer survival prognoses and were significantly linked to high-grade and advanced-stage tumors, using a variety of R software packages and web analysis tools. Furthermore, we demonstrated that the low-risk group had significant changes in their metabolic pathways. In contrast, the high-risk group was characterized by high immune cell infiltration, immune checkpoint expression, and low half-maximum inhibition concentration (IC50) values of chemotherapeutic agents. This suggests that high-risk patients may benefit more from immunotherapy and chemotherapy. In conclusion, we constructed a PANoptosis-related microRNA signature and revealed its potential significance in clinicopathological features and tumor immunity, thereby providing new precise treatment strategies.

Mitochondria are highly dynamic organelles. Through a large-scale in vivo RNA interference (RNAi) screen that covered around a quarter of the Drosophila melanogaster genes (4000 genes), we identified 578 genes whose knockdown led to aberrant shapes or distributions of mitochondria. The complex analysis revealed that knockdown of the subunits of proteasomes, spliceosomes, and the electron transport chain complexes could severely affect mitochondrial morphology. The loss of Dhpr, a gene encoding an enzyme catalyzing tetrahydrobiopterin regeneration, leads to a reduction in the numbers of tyrosine hydroxylase neurons, shorter lifespan, and gradual loss of muscle integrity and climbing ability. The affected mitochondria in Dhpr mutants are swollen and have fewer cristae, probably due to lower levels of Drp1 S-nitrosylation. Overexpression of Drp1, but not of S-nitrosylation–defective Drp1, rescued Dhpr RNAi-induced mitochondrial defects. We propose that Dhpr regulates mitochondrial morphology and tissue homeostasis by modulating S-nitrosylation of Drp1.

Metastasis contributes to around 90% of cancer mortality, but effective strategies to disrupt metastatic cascades remain elusive. Hypoxia‐driven epithelial‐mesenchymal transition (EMT) promotes cancer cell spread, yet the post‐translational mechanisms governing cytoskeletal reprogramming here remain incompletely defined. This study reports a hypoxia‐inducible post‐translational modification cascade: under hypoxia, protein arginine methyltransferase 1 (PRMT1) is lactylated at evolutionarily conserved residues K134/K145, enhancing its methyltransferase activity to catalyze the asymmetric dimethylation (aDMA) of vimentin at R64. This modification drives vimentin filament assembly, cytoskeletal remodeling, and metastasis in preclinical models. shPRMT1 or vimentin R64K mutation (methylation‐deficient) abrogates hypoxia‐enhanced migration in vitro and metastasis in vivo. Hypoxia reduces the protein levels of HDAC8 (PRMT1’s delactylase), boosting PRMT1 lactylation. PRMT1 K134R/K145R mutants (lactylation ‐ deficient) lose the ability to bind vimentin and fail to rescue filament formation. In triple‐negative breast cancer (TNBC), vimentin R64 aDMA levels correlate with advanced tumor stage and poor patient survival. PRMT1 inhibitor MS023 reduces xenograft metastasis with low toxicity. These findings establish a hypoxia‐PRMT1‐vimentin axis, identifying vimentin R64 aDMA as a metastatic regulator. Inhibiting PRMT1 represents a promising anti‐metastasis strategy.

Sora is the first-line drug for advanced hepatocellular carcinoma (HCC). However, acquired resistance to Sora treatment largely hinders its therapeutic efficacy, and the mechanisms underlying Sora resistance remain poorly understood. Here, we revealed a new mechanism by which Sora promotes the differentiation of regulatory T (Treg) cells to suppress the immune response in the HCC tumor microenvironment (TME) and induce Sora resistance. Human liver tissues were obtained from HCC patients. Female C57BL/6J, OT-II, and Foxp3^GFP mice were also used. Flow cytometry was used to analyze immune cells in TME. Flow cytometry, real-time polymerase chain reaction, and enzyme-linked immunosorbent assay were performed to evaluate Treg cell differentiation. Immunoblotting was conducted to identify relevant proteins. Mouse and human tumor tissues were evaluated via multiplex immunofluorescence staining. Sora-treated HCC tissues and Sora-treated Treg cells were subjected to RNA sequencing analysis. Tumor models were generated and treated with Sora, Sora combined with an anti-CD25 antibody, or Sora combined with the Foxo1 inhibitor AS1842856. First, we found through bioinformatic analysis that Sora suppresses the immune response in HCC. Furthermore, Sora increased the Treg cell population to promote the formation of an immunosuppressive TME in HCC. In vitro, Sora promoted Treg cell differentiation and increased the immunosuppressive activity of Treg cells. Activating VEGF and AKT abolished the effect of Sora on Treg cell differentiation, whereas inhibiting Foxo1 compromised Sora-induced Treg cell differentiation, indicating that the induction of Treg cells by Sora is dependent on the VEGFR/AKT/Foxo1 pathway. Finally, Treg inactivation by an anti-CD25 antibody or the Foxo1 inhibitor AS1842856 in combination with Sora showed greater efficacy in the treatment of HCC. Sora induced Treg cell differentiation by inhibiting VEGFR/AKT signaling and activating Foxo1, thus suppressing the immune response and reducing Sora efficacy. Treg inactivation might be a promising strategy to alleviate the immunosuppressive TME and overcome Sora resistance.

Despite advances in colorectal cancer (CRC) treatment, immunotherapy shows limited efficacy due to low immunogenicity. Nonsense-mediated mRNA decay (NMD) prevents the synthesis of potentially detrimental proteins. While targeting NMD has therapeutic potential, its specific effect on CRC remains uncertain. Our research discovered significant NMD activation and upregulated SMG5 expression in CRC. Inhibition of NMD by small interfering RNA (siRNA) targeting SMG5 or NMD inhibitor NMDI14 remodeled tumor microenvironment (TME) by altering innate immune cells and enhancing CD8⁺ T cells activation. NMD inhibition also activated TBK1 through upregulation of TRAF6, which was targeted by NMD through its elongated 3'-UTR in a non-canonical manner. High SMG5 and low TRAF6 expression are associated with poor immunotherapy response. Inhibiting NMD enhanced the effectiveness of immune checkpoint blockade (ICB) therapy in CRC. By uncovering the biological relevance and translational potential of targeting NMD to reconstruct TME, this study highlights its promise as a treatment strategy for CRC.