The DsbA-L paradox in protective and pathogenic stress adaptation

Abstract

Summary Disulfide-bond A oxidoreductase-like protein (DsbA-L), also known as glutathione S-transferase kappa 1 (GSTK1), regulates adiponectin assembly, organelle homeostasis, and cellular responses to metabolic stress. Evidence from cellular knockdown, constitutive and tissue-specific knockout models, and studies of metabolic, fibrotic, immune, and cancer contexts shows that its effects are strongly context dependent. DsbA-L can preserve metabolic homeostasis by supporting adiponectin multimerization, mitochondria-associated membrane integrity, redox control, mitophagy, and reticulophagy, yet it can also sustain profibrotic or immune-metabolic programs and show divergent effects across cancers. We propose that these observations are best understood by viewing DsbA-L as a regulator of stress adaptability whose output depends on cell identity, stress reversibility, downstream signaling, and adaptive reserve. This framework reconciles apparently conflicting findings and argues for tissue-specific modulation or downstream-effector targeting rather than indiscriminate systemic activation or inhibition.