Rgs5, or regulator of G-protein signaling 5, is a GTPase activator for heterotrimeric G-protein α -subunits. As a negative regulator of G protein-coupled receptor (GPCR) signaling, it is highly expressed in arterial VSMCs and pericytes, and is involved in various biological processes such as VSMC phenotypic heterogeneity, vascular remodeling, and regulation of arterial tone and blood pressure [3,6]. It also plays a role in GPCR-downstream PI3K-AKT signaling, apoptosis, and cytokine production [8,4].

In NASH, resmetirom, a THR-β agonist, can improve the condition by recovering RGS5 expression and inactivating the STAT3 and NF-κB signaling pathways. Silencing of RGS5 impairs the effect of resmetirom [1].

In cardiac aging, age-dependent loss of RGS5 in pericytes impairs cardiac function, induces fibrosis, and changes pericyte morphology [2].

In breast cancer, RGS5+ lymphatic endothelial cells promote metastasis and acquired drug resistance through an oxidative stress-sensing mechanism, and genetic knockdown of RGS5 prevents tumor growth and lymph node metastasis [5].

In pancreatic cancer liver metastasis, RGS5+ cancer-associated fibroblasts contribute to the formation of an immunosuppressive tumor microenvironment [7].

In the context of the tumor microenvironment, the role of RGS5 in vascular inflammation is disrupted, with its expression increased in triple-negative breast cancer tissues and tumor blood vessels [3].

In neurodegenerative diseases, RGS5 in astrocytes promotes neuroinflammation via TNF signaling, and selective ablation of Rgs5 in astrocytes mitigates the neuroinflammatory response [4].

In pulmonary arterial hypertension, RGS5 is upregulated and regulates vascular remodeling of the pulmonary microvasculature through pericytes [6].

In tumor-residing pericytes, the RGS5-TGFβ-Smad2/3 axis switches pro-to anti-apoptotic signaling, assisting tumor growth [8].

In long bones, lineage-traced RGS5 cells have osteoprogenitor capacity and contribute to new bone formation in an injury model [9].

In conclusion, Rgs5 is a crucial regulator involved in multiple biological processes and diseases. Gene knockout and other functional studies, especially those using KO mouse models, have revealed its role in diseases such as NASH, cardiac aging, cancer metastasis, neurodegenerative diseases, and pulmonary arterial hypertension. Understanding the function of Rgs5 provides insights into disease mechanisms and potential therapeutic targets.