Emerging Roles of PSTPIP2 in Autoimmunity: From Mechanism to Therapeutic Implications.

Autoimmune and autoinflammatory diseases are characterised by dysregulated immune activation and persistent inflammation, yet effective mechanism-based therapeutic targets remain limited. Proline-serine-threonine phosphatase-interacting protein 2 (PSTPIP2), a membrane-cytoskeleton-associated adaptor protein predominantly expressed in myeloid cells, has emerged as an important endogenous regulator of inflammatory responses. This review summarises the molecular structure, expression pattern and biological functions of PSTPIP2, with particular emphasis on its role in coordinating cytoskeletal remodelling, inflammatory signalling and immune-cell behaviour. We further discuss the major mechanisms through which PSTPIP2 regulates disease progression, including suppression of IL-1β maturation, inhibition of NF-κB and ERK signalling, modulation of macrophage polarisation and control of osteoclast-associated bone remodelling. In addition, recent advances in understanding the involvement of PSTPIP2 in chronic multifocal osteomyelitis, rheumatoid arthritis, SAPHO syndrome and bullous pemphigoid are reviewed, together with evidence from PSTPIP2-deficient models that has provided important mechanistic and translational insights. Finally, the potential value of PSTPIP2 as a biomarker and therapeutic target is highlighted. Overall, PSTPIP2 represents a critical immunoregulatory node linking cytoskeletal organisation to inflammatory control, and further investigation of its molecular functions may facilitate the development of precision therapies for autoimmune and autoinflammatory diseases.