SPARCL1 (SPARC-like 1) is a secreted matricellular glycoprotein that functions as a multitissue regulator of inflammation and cellular plasticity through TLR4-mediated signaling. Structurally, it is a cysteine-rich extracellular matrix protein present in plasma and tissues 1. Mechanistically, SPARCL1 activates TLR4 on target cells—including hepatocytes, macrophages, and endothelial cells—leading to NF-κB/p65 pathway activation and pro-inflammatory gene expression, particularly CCL2/MCP-1 12. SPARCL1 also promotes supporting cell plasticity in the inner ear through follistatin activation and extracellular matrix remodeling 3. Disease relevance is substantial: elevated circulating and tissue SPARCL1 correlates with nonalcoholic steatohepatitis (NASH) progression 1, early atrophic age-related macular degeneration 4, atherosclerosis 5, and severe COVID-19 pneumonia 2. SPARCL1 expression increases in response to endothelial damage across multiple contexts. Clinically, SPARCL1 antagonism via neutralizing antibodies or genetic ablation reduces hepatic inflammation and improves NASH outcomes 1, while SPARCL1 elevation in lung endothelial cells exacerbates viral pneumonia severity 2. Conversely, therapeutic SPARCL1 delivery promotes hair cell regeneration 3 and synaptic recovery 6, suggesting context-dependent therapeutic applications.