SIRT6 (Sirtuin 6)

Distinct integrated sirtuin scores thus capture subtype-specific metabolic/epigenetic states and provide robust RFS stratification across BC subtypes. These findings highlight sirtuins as integrators of longevity pathways and tumor metabolism, suggesting therapeutically exploitable vulnerabilities along NAD⁺-dependent regulatory axes.

Furthermore, Kbhb is not limited to histones; it is also widely present in nonhistones and influences various biological processes, such as protein stability, metabolic and energy homeostasis regulation, pathogen virulence regulation, transcriptional regulation, and signal transduction. This review summarizes the research progress in the field of Kbhb, including the inducers of Kbhb (ketogenic diet), prediction methods for modification sites (KbhbXG, pFunK, SLAM, iBhb-Lys), regulatory elements of modification (regulatory enzymes such as ENL and SIRT6, and protein substrates), mechanisms of action in cancer (e.g., mTOR signalling pathway, cGAS-STING signalling pathway), mechanisms of action in immune-related signalling pathways and immune-active components regulation, research progress on histone and nonhistone Kbhb (e.g., Bcl6, P53, STAT1, UvSlt2), and novel therapeutic strategies for diseases based on Kbhb modification (metabolic regulation and targeted therapy), providing new insights for targeted therapy for cancer and other diseases.

Consistently, enzymatic assays confirm a six-fold reduction in deacetylation efficiency of the L197P mutant compared with wild-type SIRT6. Collectively, our results elucidate the structural basis by which cancer-associated mutations compromise SIRT6 function, providing mechanistic insights into its allosteric regulation and potential implications for tumorigenesis.

Emerging therapeutic strategies targeting SIRT6, including small-molecule modulators, genetic interventions, and combination therapies, are critically evaluated. Our analysis underscores the necessity for context-specific therapeutic targeting, and pharmacological modulation of SIRT6 represents a promising avenue for precision oncology.

SIRT6 overexpression was linked to favorable prognosis in esophageal carcinoma and sarcoma, while unfavorable outcomes were observed in hepatocellular carcinoma and cholangiocarcinoma. SIRT7 upregulation was significantly associated with reduced survival in esophageal, liver, and uterine cancers, but surprisingly correlated with improved outcomes in urothelial carcinoma and cervical squamous cell carcinoma.ConclusionsTogether, this multi-omics analysis reveals the correlation and prognostic values of sirtuins across multiple types of human cancers and suggests that sirtuins may serve as promising biomarkers for different cancers.

SIRTs are established as crucial regulators of cancer immunity and therapy, suggesting novel directions for precision oncology. However, given their isoform- and context-dependent duality across tumor types, the clinical translation of SIRT modulators requires careful mechanistic stratification and biomarker-guided patient selection.

Our findings demonstrate that RPL7A promotes LUAD progression through circRANBP17-UPF1-mediated SIRT6 degradation, positioning RPL7A as a potential therapeutic target in LUAD.

Additionally, TFAM promotes the growth and metastasis of colon cancer in vitro and in vivo, while SIRT6 was inhibited. In conclusion, our findings provide compelling evidence that SIRT6 establishes a network linking nuclear and mitochondrial transcription through the regulation of TFAM, identifying TFAM as a potential therapeutic target for cancer.

Therefore, we investigated the interactions between the ligands quercetin (QUE), isoquercetin (ISO), catechin gallate (CG), and trichostatin A (TSA) with SIRT6, using computational methods from the perspective of molecular modeling through the Molecular Fractionation with Caps Conjugates (MFCC) technique and according to the calculation parameters of Density Functional Theory (DFT)...In addition, residues such as PRO62, MET136, MET157, and VAL115 stand out as key components of the protein active site. These findings offer strategic insights into the molecular mechanisms underlying the binding of the studied ligands to SIRT6, providing a deep understanding of their affinity and pharmacological potential.

Notably, targeting this axis with the SIRT6 inhibitor OSS-128167 combined with CAPZA1 depletion significantly suppresses ccRCC cell growth. Our study reveals a PAT-derived lipid metabolite-fuelled signaling cascade that reprograms lipid metabolism in ccRCC, identifying CAPZA1/USP48/SIRT6 as actionable therapeutic targets for metabolic malignancies.

Notably, administration of the selective NOPr antagonist UFP-101 abolished N/OFQ-induced cellular senescence, indicating that this effect is NOPr-dependent. These findings suggest that N/OFQ-NOPr signaling promotes GBM senescence via SIRT6 downregulation, highlighting a potential therapeutic target for modulating senescence in GBM.