Sirtuins as mediators and targets of arsenic toxicity: unraveling signaling pathway crosstalk

Arsenic, a widespread environmental contaminant, threatens millions globally through contaminated water, soil, and food. While arsenic compounds are used to treat acute promyelocytic leukemia, their toxic legacy includes cancers, cardiovascular disease, diabetes, and neurodegeneration, primarily driven by oxidative stress, mitochondrial dysfunction, and epigenetic instability. Sirtuins, a family of NAD⁺-dependent enzymes, are central to cellular defense, orchestrating metabolism, stress resistance, DNA repair, and longevity. Arsenic disrupts sirtuin function, particularly SIRT1, SIRT2, and SIRT3, via microRNA-mediated silencing and post-translational modifications, impairing antioxidant defenses, disturbing energy metabolism, and accelerating cellular injury across organ systems. However, activating sirtuins with agents like resveratrol, metformin, or berberine, as well as through lifestyle interventions, can counteract arsenic toxicity, restore cellular resilience, and provide new therapeutic strategies. This review synthesizes current knowledge on the interplay between arsenic exposure and sirtuin biology, examining how arsenic alters sirtuin expression and activity, the downstream consequences for cellular signaling and organ health, and emerging interventions targeting sirtuin pathways. By bridging molecular insights with translational potential, we highlight the promise of sirtuins as therapeutic targets in combating arsenic toxicity and guide future research directions.