In humans, the cytosolic glutathione S-transferase (GST) family of proteins is encoded by 16 genes presented in seven different classes. GSTs exhibit remarkable structural similarity with some overlapping functionalities. As a primary function, GSTs play a putative role in Phase II metabolism by protecting living cells against a wide variety of toxic molecules by conjugating them with the tripeptide glutathione. This conjugation reaction is extended to forming redox sensitive post-translational modifications on proteins: S-glutathionylation. Apart from these catalytic functions, specific GSTs are involved in the regulation of stress-induced signaling pathways that govern cell proliferation and apoptosis. Recently, studies on the effects of GST genetic polymorphisms on COVID-19 disease development revealed that the individuals with higher numbers of risk-associated genotypes showed higher risk of COVID-19 prevalence and severity. Furthermore, overexpression of GSTs in many tumors is frequently associated with drug resistance phenotypes. These functional properties make these proteins promising targets for therapeutics, and a number of GST inhibitors have progressed in clinical trials for the treatment of cancer and other diseases.

Low back pain is a widespread condition that significantly impacts quality of life, with intervertebral disc degeneration (IDD) being a major contributing factor. However, the underlying mechanisms of IDD remain poorly understood, necessitating further investigation. Environmental risk factors, such as mechanical stress and cigarette smoke, elevate reactive oxygen species levels from both endogenous and exogenous sources, leading to redox imbalance and oxidative stress. The endoplasmic reticulum (ER) and mitochondria, two key organelles responsible for protein folding and energy production, respectively, are particularly vulnerable to oxidative stress. Under oxidative stress conditions, ER stress and mitochondrial dysfunction occur, resulting in unfolded protein response activation, impaired biosynthetic processes, and disruptions in the tricarboxylic acid cycle and electron transport chain, ultimately compromising energy metabolism. Prolonged and excessive ER stress can further trigger apoptosis through ER–mitochondrial crosstalk. Given the unique microenvironment of the intervertebral disc (IVD)—characterized by hypoxia, glucose starvation, and region-specific cellular heterogeneity—the differential effects of environmental stressors on distinct IVD cell populations require further investigation. This review explores the potential mechanisms through which environmental risk factors alter IVD cell activities, contributing to IDD progression, and discusses future therapeutic strategies aimed at mitigating disc degeneration.

Effective cancer therapies simultaneously restrict tumor cell growth and improve anti-tumor immune responses. Targeting redox-dependent protein folding enzymes within the endoplasmic reticulum (ER) is an alternative approach to activation of the unfolded protein response (UPR) and a novel therapeutic platform to induce malignant cell death. E64FC26 is a recently identified protein disulfide isomerase (PDI) inhibitor that activates the UPR, oxidative stress, and apoptosis in tumor cells, but not normal cell types. Given that targeting cellular redox homeostasis is a strategy to augment T cell tumor control, we tested the effect of E64FC26 on healthy and oncogenic T cells. In stark contrast to the pro-UPR and pro-death effects we observed in malignant T cells, we found that E64FC26 improved viability and limited the UPR in healthy T cells. E64FC26 treatment also diminished oxidative stress and decreased global PDI expression in normal T cells. Oxidative stress and cell death are limited in memory T cells and we found that PDI inhibition promoted memory traits and reshaped T cell metabolism. Using adoptive transfer of tumor antigen-specific CD8 T cells, we demonstrate that T cells activated and expanded in the presence of E64FC26 control tumor growth better than vehicle-matched controls. Our data indicate that PDI inhibitors are a new class of drug that may dually inhibit tumor cell growth and improve T cell tumor control.

Identifying factors that contribute to the age-related onset of chronic obstructive pulmonary disease (COPD) is crucial for its prevention and treatment. The multifunctional endoplasmic reticulum (ER) chaperone protein disulfide isomerase A1 (PDIA1) shows a protective increase in expression levels in human and mouse non-COPD smokers. However, this increase slows with aging and disease progression, while increase in glutathione S-transferase π1 (GSTP1) does not. PDI has redox sensitive cysteine residues that can become S-glutathionylated (PDI-SSG) which compromise both isomerase and chaperone activity. Oxidized PDIA1 levels progressively rise with age in the lungs of murine non-smokers, with an even greater increase in smokers. To investigate whether an increased oxidized-to-native PDIA1 ratio (PDI-SSG/PDI-SH) contributes to the depletion of alveolar epithelial type 2 progenitor cells in COPD, we used the type-2-like cell line MLE12. High doses of cigarette smoke (CS) induced elevated oxidized PDIA1 levels, while a redox-refractory PDIA1 variant maintained a lower PDI-SSG/PDI-SH. Upon CS exposure, PDIA1 was S-glutathionylated by GSTP1 and predominantly localized at the ER-mitochondria interface. This mitochondrial proximity was prevented by pharmacological or genetic GSTP1 inhibition. When localized at the ER-mitochondria interface, S-glutathionylated PDIA1 decreased mitochondrial membrane potential (MMP), facilitated mitochondrial permeability transition pore opening, decreased mitochondrial respiration and triggered cytochrome c (Cyt c) release, followed by caspase-3 activation. Isolated mitochondrial studies confirmed that PDI-SSG trigger these apoptotic signals whereas native PDI does not. Our findings indicate that GSTP1-mediated S-glutathionylation of PDIA1 drives pro-apoptotic intraorganellar signaling by altering its ER distribution. Overexpression of a redox-refractory PDIA1 variant restored MMP and reduced Cyt c release, suggesting that a lower S-glutathionylated-to-native PDIA1 ratio is protective. These findings highlight a threshold-dependent regulation of PDIA1-SSG/PDIA1-SH redox signaling. We propose that the simultaneous inability to maintain high PDIA1 levels and the age-associated increase in its S-glutathionylated form in smokers accelerates AEC2 depletion and exhaustion, thereby contributing to emphysema progression.