Abstract: Human serum albumin (HSA), the most abundant circulating protein in human plasma, is exclusively synthesized by hepatic parenchymal cells. HSA undergoes a broad spectrum of enzymatic and non-enzymatic post-translational modifications (PTMs), which induce substantive conformational alterations to the protein backbone. The physiological functions of HSA include maintenance of plasma colloid osmotic pressure, ligand binding and transport, endogenous antioxidant activity, anti-inflammatory effects, etc. Critically, the biological functions of HSA are intrinsically coupled to its three-dimensional conformational state. Across a wide range of pathological conditions, disease-driven perturbations to HSA structure compromise its biological functionality, which in turn modifies disease trajectory and modulates the therapeutic efficacy of clinical interventions. Currently, plasma-derived HSA (pdHSA), purified from the plasma of healthy human donors, is ubiquitously administered in the clinical management of diverse critically ill patient populations. With recent transformative advances in biopharmaceutical technology, recombinant HSA (rHSA) has been successfully translated into clinical practice, with demonstrable differences in structural properties, biological functionality, and safety profiles relative to pdHSA. This review synthesizes the core PTMs and functional regulatory mechanisms of HSA, delineates disease-associated alterations in HSA structure and function across multiple pathological states, and directly compares the structural and functional similarities and differences between pdHSA and rHSA. Collectively, this article provides a comprehensive, integrated framework for understanding HSA biology, establishing a foundational theoretical basis for the innovative clinical application of HSA-based therapeutics and the advancement of precision medicine practice.

Key words: Human serum albumin, Post-translational modifications, Functional regulation, Disease associations, Plasma-derived human serum albumin, Recombinant human serum albumin