Updated project metadata. The dynamic environment of the rocky intertidal has long been used as model for understanding the physiological capacity of marine species, particularly with respect to climate change. The innate environmental variability—particularly thermal extremes—has provided insight into the cellular stress response and mechanisms underlying thermal tolerance in intertidal invertebrates. Food availability is known to play a role in thermal tolerance, and recently studies have shown that well-fed mussels perform as well as those having undergone thermal conditioning following an acute heat shock, suggesting an interesting interplay between food and previous history. Underlying the food-by-temperature dependence of the heat shock response, there is evidence that sirtuins, which are a class of NAD + -dependent deacylases, serve as a mechanistic link. In this study, we evaluated the effects of two sirtuin inhibitors (e.g., nicotinamide and suramin) and a subsequent heat shock exposure (33 ºC) on the gill proteome of the California mussel, Mytilus californianus. To explicitly test the interaction between food and previous thermal environment on the heat shock response, we used mussels acclimated to two daily food rations (0.25 and 1.25 % g -1 dry weight) and two daytime, aerial temperatures (20 and 30 ºC). Protein abundance was measured for mussels prior to inhibition and heat shock and at two time points (e.g., 1 and 25 hr) during the recovery phase using a label-free LC-MS/MS approach. Sirtuin inhibition prior to heat shock altered the proteomic response in an acclimation-dependent manner, with mussels acclimated to low food and low temperature (LTLF) largely maintaining the extensive metabolic, antioxidant, proteostatic, and cytoskeletal responses previously observed during heat shock alone. In contrast, mussels acclimated to high food and high temperature (HTHF) exhibited widespread decreases in the same protein groups, indicating a fundamentally different recovery strategy. Collectively, these findings demonstrate that food availability and sirtuin activity jointly modulate the cellular stress response in M. californianus. By influencing metabolism, redox balance, proteostasis, and cytoskeletal stability, sirtuins appear to integrate energetic state with thermal stress responses, providing a mechanistic explanation for previously observed links between nutrition and thermal tolerance in intertidal mussels.