Targeting p66Shc by natural-derived and synthetic compounds in organ toxicity
Fatemeh Yarmohammadi, Sasan Shabani, Gholamreza KarimiIntroduction
The p66Shc protein functions as a cellular stress sensor that facilitates the elimination of irreversibly damaged cells under physiological conditions. However, during chronic stress, this pathway becomes maladaptive, contributing to progressive tissue degeneration. The present study reviews the involvement of p66Shc as an intracellular amplifier of organ toxicity triggered by various chemical and environmental agents, including arsenite, cisplatin, ethanol, nicotine, doxorubicin, acrolein, and UVB radiation.
Methods
A narrative literature review was conducted using PubMed, Scopus, and Web of Science with the search query: (“p66Shc” OR “p66 Src collagen homologue”) AND (protective OR protection OR prevent OR prevention OR ameliorate OR amelioration OR attenuate OR attenuation), and relevant studies were synthesized narratively.
Results
These toxicants predominantly induce tissue injury in the heart, kidneys, liver, central nervous system, ovaries, skin, and developing embryos. Activation of the p66Shc pathway is driven by phosphorylation at Ser36 and mitochondrial translocation, which amplifies reactive oxygen species (ROS) generation by disrupting redox balance in the electron transport chain. Excessive ROS subsequently leads to oxidative stress, apoptosis, inflammation, and progressive cellular dysfunction. Several bioactive compounds have demonstrated modulatory effects on p66Shc signaling. For instance, berberine and carnosic acid attenuate p66Shc activity via SIRT1 activation; ginkgolide B downregulates p66Shc mRNA expression through microRNA-mediated pathways; resveratrol enhances the p66Shc/Nrf2/HO-1 signaling axis to strengthen antioxidant defenses; and coenzyme Q10 inhibits phosphorylation-dependent activation of p66Shc.
Discussion
Collectively, this study identifies p66Shc as a promising therapeutic target for mitigating organ injuries caused by environmental toxicants. However, the available evidence is predominantly derived from preclinical studies with limited human data. Moreover, the lack of isoform-selective p66Shc inhibitors and the heterogeneity of experimental designs constrain the generalizability of current findings.