Although essential for life, copper is also potentially toxic in concentrations that surpass physiological thresholds. The high-osmolarity glycerol pathway of yeast is the main regulator of adaptive responses and is known to play crucial roles in the responses to various stressors. The objective of this research is to determine whether the HOG pathway could be activated and to investigate the possible interplay of the HOG pathway and oxidative stress due to copper exposure. In this research, we demonstrate that copper could induce oxidative stress, including the elevated concentrations of reactive oxygen species (ROS) and malondialdehyde (MDA). Increased combination with GSH, increased intracellular SOD activity, and the up-regulation of relevant genes can help cells defend themselves against oxidative toxicity. The results show that copper treatment triggers marked and prolonged Hog1 phosphorylation. Significantly, oxidative stress generated by copper toxicity is essential for the activation of Hog1. Activated Hog1 is translocated to the nucleus to regulate the expressions of genes such as CTT1, GPD1, and HSP12, among others. Furthermore, copper exposure induced significant G1-phase cell cycle arrest, while Hog1 partially participated in the regulation of cell cycle progression. These novel findings reveal another role for Hog1 in the regulation of copper-induced cellular stress.

During growth and metabolism, the budding yeast Saccharomyces cerevisiae is continuously exposed to diverse environmental stresses, and conserved mitogen-activated protein kinase (MAPK) cascades execute core functions in stress sensing and adaptive regulation. The high-osmolarity glycerol (HOG) pathway, a classical MAPK cascade in S. cerevisiae, was initially identified as the core regulator of hyperosmotic stress responses. Over recent decades, accumulating evidence has revealed that the HOG pathway is not merely an osmoregulatory module but a versatile signaling hub that integrates multiple stress inputs and orchestrates a broad spectrum of adaptive responses. This review systematically summarizes the core architecture of the HOG pathway, including its upstream sensing branches (Sln1 and Sho1) and the conserved three-tiered MAPK cascade, with an emphasis on how different stressors engage distinct branches and lead to differential Hog1 phosphorylation kinetics. This review further discusses the multifaceted roles of the HOG pathway in stress adaptation, covering transcriptional reprogramming, cell cycle arrest, metabolic reprogramming centered on glycerol synthesis, and emerging functions such as cell wall remodeling, flocculation, mitophagy, and cross-talk with other MAPK pathways. By integrating classical and contemporary findings, this review presents a comprehensive view of the HOG pathway in S. cerevisiae and provides a reference for future research on stress signaling and engineering of this model organism.