Cellular low-molecular-weight thiol (LMWT)

Cellular low-molecular-weight (LMW) thiols are a vital class of sulfur-containing small molecules, including glutathione (GSH), cysteine, homocysteine, and coenzyme A, that maintain the intracellular redox environment [1, 4, 12]. They function as nucleophilic scavengers that neutralize reactive oxygen species (ROS) and electrophilic xenobiotics, often serving as essential cofactors for enzymes like glutathione peroxidases and S-transferases [10, 14]. Beyond protection, LMW thiols regulate cellular signaling and protein function through reversible S-thiolation, which prevents irreversible oxidative damage to protein-bound cysteines [6, 10, 13]. In clinical practice, LMW thiols are targeted to address conditions characterized by oxidative stress, such as chronic inflammation, neurodegeneration, and acetaminophen toxicity [8, 9, 17]. Drugs like N-acetylcysteine act as prodrugs to replenish depleted glutathione pools, while others like buthionine sulfoximine are investigated for their ability to sensitize cancer cells to treatment by exhausting their antioxidant defenses [2, 9, 15]. Maintaining the balance of these thiols is crucial, as both excessive depletion and excessive accumulation (reductive stress) can impair normal cellular physiology [11, 18].

Other names

Low-molecular-weight thiolsSmall-molecule thiolsBiothiolsNon-protein thiolsNPSHLow-molecular-weight biothiols

Pharmacological modulation of cellular low-molecular-weight thiols involves three primary strategies: supplementation of biosynthetic precursors like N-acetylcysteine to bolster glutathione levels [9, 11, 16], direct scavenging of reactive oxygen and nitrogen species by thiol-containing drugs [9, 12], and targeted depletion of thiol pools using agents such as buthionine sulfoximine to increase cellular sensitivity to oxidative stress and chemotherapy [2, 15].