The sirtuin family: from mechanisms to therapy.
5 affiliations
- 1Department of Gastroenterology, Shengjing Hospital Affiliated to China Medical University, Shenyang, China.
- 2Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang, China.
- 3Times Joyee (Liaoning) Information Co., Ltd, Shenyang, China.
- 4Department of Urology, Urologic Surgery Centre, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
- 5Department of Medical Genetics, China Medical University, Shenyang, China. [email protected].
Abstract
Sirtuins (SIRT1-SIRT7) are evolutionarily conserved NAD⁺-dependent deacylases that function as metabolic sensors, coupling cellular metabolic state to epigenetic, transcriptional and post-translational regulatory programs across distinct subcellular compartments. Despite two decades of research, isoform- and disease-specific aspects remain poorly integrated, limiting both conceptual clarity and therapeutic translation. This review synthesizes recent advances in sirtuin biology into a family-wide framework. Rather than functioning as isolated longevity factors, sirtuins operate as a distributed compartmentalized regulatory network in which nuclear SIRT1, SIRT6 and SIRT7, cytosolic SIRT2 and mitochondrial SIRT3, SIRT4 and SIRT5 collectively govern glucose and lipid metabolism, mitochondrial quality control, autophagy, inflammation and immune tolerance. This network operates across metabolic disorders, cardiovascular and neurodegenerative diseases, inflammatory conditions and cancer, where dysregulated sirtuin signalling influences disease development in a disease- and tissue-specific manner. Therapeutic strategies are evaluated, ranging from isoform-selective small-molecule modulators and NAD⁺-targeted interventions to emerging protein-degradation approaches, with isoform selectivity, off-target effects and the systemic consequences of NAD⁺ modulation identified as key translational barriers that have contributed to heterogeneous clinical outcomes. Viewing sirtuins as a context-sensitive compartmentalized network, not isolated targets, offers a coherent framework to guide mechanistic interrogation and the design of more precise sirtuin-based therapies, with priority areas including tissue-selective degradation and network-level biomarkers.
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BibTeX
@article{xiao2026sirtuin,
title = {{The sirtuin family: from mechanisms to therapy.}},
author = {Jiaying Xiao and Yiling Li and Yuyao Xie and Yuan Chen and Qihan Liu and Hao Li and Rui Sun},
journal = {Molecular biomedicine},
year = {2026},
month = oct,
doi = {10.1186/s43556-026-00631-0},
url = {https://europepmc.org/article/MED/42909727},
note = {CC BY},
}
RIS
TY - JOUR
TI - The sirtuin family: from mechanisms to therapy.
AU - Jiaying Xiao
AU - Yiling Li
AU - Yuyao Xie
AU - Yuan Chen
AU - Qihan Liu
AU - Hao Li
AU - Rui Sun
PY - 2026
DA - 2026/10/23
JO - Molecular biomedicine
DO - 10.1186/s43556-026-00631-0
UR - https://europepmc.org/article/MED/42909727
AB - Sirtuins (SIRT1-SIRT7) are evolutionarily conserved NAD⁺-dependent deacylases that function as metabolic sensors, coupling cellular metabolic state to epigenetic, transcriptional and post-translational regulatory programs across distinct subcellular compartments. Despite two decades of research, isoform- and disease-specific aspects remain poorly integrated, limiting both conceptual clarity and therapeutic translation. This review synthesizes recent advances in sirtuin biology into a family-wide framework. Rather than functioning as isolated longevity factors, sirtuins operate as a distributed compartmentalized regulatory network in which nuclear SIRT1, SIRT6 and SIRT7, cytosolic SIRT2 and mitochondrial SIRT3, SIRT4 and SIRT5 collectively govern glucose and lipid metabolism, mitochondrial quality control, autophagy, inflammation and immune tolerance. This network operates across metabolic disorders, cardiovascular and neurodegenerative diseases, inflammatory conditions and cancer, where dysregulated sirtuin signalling influences disease development in a disease- and tissue-specific manner. Therapeutic strategies are evaluated, ranging from isoform-selective small-molecule modulators and NAD⁺-targeted interventions to emerging protein-degradation approaches, with isoform selectivity, off-target effects and the systemic consequences of NAD⁺ modulation identified as key translational barriers that have contributed to heterogeneous clinical outcomes. Viewing sirtuins as a context-sensitive compartmentalized network, not isolated targets, offers a coherent framework to guide mechanistic interrogation and the design of more precise sirtuin-based therapies, with priority areas including tissue-selective degradation and network-level biomarkers.
SN - 2662-8651
ER -