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

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Sirtuins (SIRTs) are NAD+-dependent enzymes with diverse roles in cellular processes, including metabolism, gene regulation, and cancer.
• A paradox exists where SIRTs can both inhibit and promote cancer depending on the cellular context.

Purpose of the Study:

• To reframe the paradoxical roles of SIRTs in cancer as context-dependent.
• To define a 'SIRT context code' that integrates various factors influencing SIRT function.
• To review evidence on how SIRTs regulate key cancer processes and therapy responses.

Main Methods:

• Literature review of mechanistic and translational evidence on SIRT function in cancer.
• Definition of a 'SIRT context code' encompassing NAD+ levels, localization, PTMs, and tumor microenvironment.
• Analysis of SIRT roles in metabolic switching, epigenetics, and cancer progression.

Main Results:

• SIRT output is determined by a complex interplay of cellular and microenvironmental factors.
• SIRTs regulate metabolic adaptation, epigenetic modifications (acetylation, lactylation), genome stability, and immune evasion.
• SIRTs influence cancer stem cell plasticity, angiogenesis, and resistance to various cancer therapies.

Conclusions:

• Sirtuin pharmacology requires context-specific targeting rather than broad activation or inhibition.
• Future priorities include developing isoform-selective agents and spatial biomarkers.
• SIRT modulators are promising but require clinical validation through biomarker-stratified trials.