Sparcl1, also known as High endothelial venule protein/SPARC-like 1 (hevin), is a secreted glycoprotein belonging to the Sparc family of matricellular proteins. It is involved in regulating cell adhesion, migration, and proliferation, and plays a role in tissue remodeling during embryogenesis and adult life. It functions through multiple pathways, such as binding to Toll-like receptor 4 (TLR4) and activating the NF-κB/p65 signaling pathway, as well as the TNF/NF-κB pathway [1,3].

Genetic ablation of Sparcl1 in mice has shown significant impacts. In non-alcoholic steatohepatitis (NASH), genetic ablation of Sparcl1, knockdown of Sparcl1 in white adipose tissue, and treatment with a Sparcl1-neutralizing antibody dramatically alleviated diet-induced NASH pathogenesis. Sparcl1 promoted NASH progression through upregulating C-C motif chemokine ligand 2 (CCL2) in hepatocytes [1]. In viral pneumonia, endothelial deletion of Sparcl1 alleviated detrimental lung inflammation, while endothelial overexpression promoted it by inducing 'M1-like' macrophages and related pro-inflammatory cytokines [2,5]. In osteoarthritis, intra-articular injection of recombinant Sparcl1 protein in an anterior cruciate ligament transection mouse model promoted OA pathogenesis, and the activation of the TNF/NF-κB pathway by Sparcl1 led to increased transcription of inflammatory factors and catabolism genes of cartilage [3]. In neuropathic pain, hevin-null mice (lacking Sparcl1) exhibited reduced inflammatory pain and faster recovery from neuropathic pain after nerve injury, and intrathecal injection of a neutralizing Ab against hevin alleviated various types of pain [4].

In conclusion, Sparcl1 is a crucial protein involved in multiple biological processes and disease conditions. Gene knockout (KO) mouse models have revealed its role in NASH, viral pneumonia, osteoarthritis, and neuropathic pain. These findings suggest that Sparcl1 could be a potential therapeutic target for treating these diseases.