T-Cell Immunosenescence in Systemic Lupus Erythematosus: Molecular Mechanisms and Therapeutic Perspectives.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by chronic immune activation, relapsing-remitting clinical progression, and progressive multi-organ damage. In addition to the classical characteristics of autoantibodies and immune complexes, emerging evidence highlights T-cell immunosenescence as a key factor in SLE pathogenesis. In this review, we elucidate the phenotypic and molecular landscapes of immunosenescent T cells in SLE, highlighting the core cellular programs that reshape their functional identity, including cell cycle arrest, dysregulated apoptosis, oxidative stress and DNA damage, mitochondrial reprogramming, and senescence-associated secretory phenotype (SASP). By integrating these mechanistic insights, we propose an immunosenescence-inflammation vicious cycle in SLE, focusing on how an expanded pool of immunosenescent T cells emerges and how mitochondrial dysfunction sustains this loop. In parallel, we elucidate the molecular crosstalk between inflammatory signaling pathways of SLE and immunosenescence programs. Moreover, evidence linking T-cell immunosenescence to SLE complications, including cardiovascular and metabolic comorbidities, as well as other systemic manifestations, is summarized. Finally, we outline therapeutic perspectives that target T-cell immunosenescence. Specifically, we discuss senolytics (for instance, dasatinib, quercetin, and fisetin) designed to selectively eliminate senescent cells, and senomorphics (for instance, rapamycin and Janus kinase inhibitors) designed to suppress the SASP and improve mitochondrial function, while discussing practical considerations for clinical translation. These advances underscore the potential of biomarker-guided patient stratification for future precision interventions in SLE.