New insights into the suppression of inflammation and lipid accumulation by JAZF1

Atherosclerosis is one of the leading causes of disease and death worldwide. The identification of new therapeutic targets and agents is critical. JAZF1 is expressed in many tis-sues and is found at particularly high levels in adipose tissue (AT). JAZF1 suppresses inflamma-tion (including IL-1b, IL-4, IL-6, IL-8, IL-10, TNFa, IFN-g, IAR-20, COL3A1, laminin, and MCP-1) by reducing NF-kB pathway activation and AT immune cell infiltration. JAZF1 reduces lipid accumulation by regulating the liver X receptor response element (LXRE ) of the SREBP-1c pro -moter, the cAMP-response element (CRE ) of HMGCR, and the TR4 axis. LXRE and CRE sites are present in many cytokine and lipid metabolism gene promoters, which suggests that JAZF1 reg-ulates these genes through these sites. NF-kB is the center of the JAZF1-mediated inhibition of the inflammatory response. JAZF1 suppresses NF-kB expression by suppressing TAK1 expres-sion. Interestingly, TAK1 inhibition also decreases lipid accumulation. A dual-targeting strategy of NF-kB and TAK1 could inhibit both inflammation and lipid accumulation. Dual-target com-pounds (including prodrugs) 1-5 exhibit nanomolar inhibition by targeting NF-kB and TAK1, EGFR, or COX-2. However, the NF-kB suppressing activity of these compounds is relatively low (IC50 > 300 nM). Compounds 6-14 suppress NF-kB expression with IC50 values ranging from 1.8 nM to 38.6 nM. HS-276 is a highly selective, orally bioavailable TAK1 inhibitor. Combined structural modifications of compounds using a prodrug strategy may enhance NF-kB inhibition. This review focused on the role and mechanism of JAZF1 in inflammation and lipid accumula-tion for the identification of new anti-atherosclerotic targets. 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).

Automated summary

Atherosclerosis is a major global health issue, and the identification of new therapeutic targets and agents is crucial. The gene JAZF1 has been found to play a role in suppressing inflammation and reducing lipid accumulation in adipose tissue. It acts by inhibiting NF-kB pathway activation and immune cell infiltration, and regulating genes involved in cytokine and lipid metabolism.