Targeting STAT3 in systemic lupus erythematosus and lupus nephritis: mechanisms, therapeutic advances, and...

This review summarizes the mechanistic and therapeutic relevance of Signal Transducer and Activator of Transcription 3 (STAT3) in systemic lupus erythematosus (SLE) and lupus nephritis (LN), with an emphasis on how structural information can inform drug development. STAT3 integrates cytokine- and growth factor-driven JAK-STAT signaling, supports pathological T cell differentiation, B cell activation, and renal inflammation, and has therefore emerged as a potential therapeutic node in lupus. Current pharmacological evidence includes traditional Chinese medicine-derived compounds, repurposed or conventional immunomodulators, and clinically advancing JAK-STAT pathway inhibitors; however, most agents act through upstream or indirect modulation rather than direct STAT3 targeting. Structure-informed analyses of candidate compounds further suggest differential druggability across STAT3 domains, with the CCD and SH2 domain providing plausible binding surfaces, whereas the DBD remains comparatively inaccessible. Together, current evidence supports STAT3 as a mechanistically important and therapeutically tractable axis in SLE and LN, while highlighting the need for biochemical, cellular, and in vivo validation of domain-selective inhibitors, dual-domain engagement strategies, and degrader-based approaches.