SIRT Family: Biological Functions and Therapeutic Targets

Experimental approaches for investigating sirtuin-mediated mitochondrial function, cellular metabolism, and epigenetic regulation.

Decoding Context-Dependent Sirtuin Pharmacology in Cancer: Metabolic-Epigenetic Switches and Precision Therapeutic Targeting.

Sirtuins (SIRT1-SIRT7) are a family of NAD+-dependent lysine deacetylases that possess mono-ADP-ribosyltransferase activity and integrate cellular metabolic status with chromatin regulation, genome maintenance, redox homeostasis, immune responses, and adaptation to cancer therapies. Their translational value has been obscured by a recurring paradox: the same isoform may constrain malignant transformation in one setting yet support metastatic competence, stemness, immune evasion, or drug resistance in another. This review reframes that paradox as a measurable problem of context. We define a SIRT context code in which NAD+ availability and compartmentalization, subcellular localization, PTM state, chromatin occupancy, oncogenic genotype, cell lineage, and tumor microenvironment jointly determine sirtuin output. Using recent mechanistic and translational evidence, we summarize how sirtuins regulate metabolic switching, histone acetylation and lactylation, genome stability, cancer-associated fibroblast programs, regulatory T-cell enrichment, cancer stem-cell plasticity, angiogenesis, and resistance to DNA-damaging, targeted, and immune therapies. We further argue that successful sirtuin pharmacology will require context matching rather than indiscriminate activation or inhibition. Priorities include spatial and single-cell biomarker discovery, compartment-specific NAD+ measurements, PTM-resolved activity assays, structure-guided isoform-selective agents, and degrader strategies targeting non-catalytic scaffolding functions. Sirtuins should therefore be viewed as metabolic-epigenetic decision nodes rather than fixed oncogenes or tumor suppressors. However, the evidence remains predominantly preclinical, and our search identified no clinical-stage oncology trials of direct sirtuin modulators using prospective biomarker stratification, underscoring that this framework remains translationally aspirational rather than clinically validated.

SIRT5/7 desuccinylation in cancer: linking metabolism, immunity, and drug resistance.

The sirtuin family proteins SIRT5 and SIRT7, as NAD⁺-dependent lysine desuccinylases, exert critical yet context-dependent roles in cancer progression. Mitochondrial SIRT5 functions as a metabolic rheostat, desuccinylating key enzymes in the TCA cycle, glutaminolysis, and fatty acid oxidation to maintain redox balance and bioenergetic output. Conversely, nuclear SIRT7 acts as an epigenetic modulator, regulating chromatin architecture and DNA damage repair via histone and non-histone desuccinylation. These compartmentalized activities converge to coordinate a metabolic-epigenetic axis that drives tumor adaptation to metabolic stress, evasion of immune surveillance, and therapeutic resistance. Given this functional duality, biomarker-guided therapeutic strategies are imperative. This review synthesizes the emerging roles of SIRT5/7-mediated desuccinylation in cancer metabolism, immunity, and drug resistance, highlighting their potential as targets for synergistic metabolic-immunotherapy interventions.

Deciphering the role of sirtuins in cancer immunoregulation through molecular cross-talk and docking-based interaction

The modulatory role of Sirtuins in FOXP3 expression and Treg differentiation is reviewed, providing insight into their contribution to tumor immunosuppression and integrating network-based analysis identified miR-34a as a central regulator and validated the miRNA-Transcription Factor-Sirtuin axis as a viable framework for cancer therapeutic targeting.

Advances in sirtuin research in lung diseases (Review)

Sirtuins, which comprise a family of NAD+-dependent deacetylases, have emerged as critical regulators in the pathogenesis of pulmonary diseases because of their pleiotropic roles in oxidative stress, metabolic homeostasis and inflammation. Growing evidence indicates that sirtuins modulate key cellular processes, including mitochondrial function, cell survival and death pathways, via protein deacetylation, thereby influencing disease progression in chronic obstructive pulmonary disease, pulmonary fibrosis and lung cancer. Notably, dysregulated sirtuin expression and activity are implicated in various lung pathologies, highlighting their dual potential as diagnostic biomarkers and therapeutic targets. The present review synthesized recent advances in sirtuin research, focusing on molecular mechanisms and translational applications, to provide a foundation for developing novel strategies for lung disease prevention and treatment. A comprehensive literature review of the relationship between sirtuins and lung-related diseases was conducted. Literature published in PubMed and Web of Science up to May 2025 was searched using the keywords 'sirtuin,' 'SIRTs,' 'lung disease,' and 'pulmonary disease.'

Emerging roles of SIRT6 and its modulators in kidney diseases.

The global incidence and prevalence of kidney diseases continue to rise, posing a serious public health challenge. SIRT6 is an NAD⁺-dependent histone deacetylase with broad essential regulatory roles across various pathophysiological processes, including DNA repair, chromatin accessibility, telomere stability, and glycolipid metabolism. As an epigenetic regulator specifically expressed in kidney tissues, SIRT6 serves as a central mediator of kidney homeostasis. Notably, accumulating evidence has implicated aberrant SIRT6 expression in the onset and development of various kidney diseases, such as acute kidney injury, diabetic kidney disease, hypertensive nephropathy, renal fibrosis, and renal cell carcinoma. In the present review, we provide an overview of the sirtuin family, systematically characterize the enzymatic activities and critical biological functions of SIRT6, and discuss its molecular mechanisms across various kidney diseases, focusing on its cell type-specific functions. We further summarize the latest research advances in SIRT6-targeted modulators for improving kidney diseases and analyze the challenges associated with their clinical application. Overall, we highlight SIRT6 as a highly promising novel target in the treatment and prevention of kidney diseases, with strong potential for clinical translation.