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조회187

충북대학교 약학대학

Metab.-Clin. Exp., Dec 26 2024, S0026-0495(24)00342-1 | https://doi.org/10.1016/j.metabol.2024.156114 A3AR antagonism mitigates metabolic dysfunction-associated steatotic liver disease by exploiting monocyte-derived Kupffer cell necroptosis and inflammation resolution

Jeong-Su Park ^a,1, Yuan-Qiang Ma ^a,1, Feng Wang ^a, Hwan Ma ^a, Guoyan Sui ^a, Nodir Rustamov ^a, Minyeong Han ^a, Yejin Son ^a, Chun-Woong Park^a, Sang-Bae Han ^a, Jin Tae Hong ^a, Lak Shin Jeong ^b,c, Jin Lee ^d, Yoon Seok Roh ^a

^aCollege of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, South Korea
^bResearch and Development Center, Future Medicine Co., Ltd, Seongnam, South Korea
^cCollege of Pharmacy, Seoul National University, Seoul, South Korea
^dDepartment of Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA

¹These authors contributed equally to this work.
Corresponding authors: Jin Lee, Yoon Seok Roh

Abstract

Metabolic dysfunction-associated steatotic liver (MASLD) progression is driven by chronic inflammation and fibrosis, largely influenced by Kupffer cell (KC) dynamics, particularly replenishment of pro-inflammatory monocyte-derived KCs (MoKCs) due to increased death of embryo-derived KCs. Adenosine A3 receptor (A3AR) plays a key role in regulating metabolism and immune responses, making it a promising therapeutic target. This study aimed to investigate the impact of selective A3AR antagonism for regulation of replenished MoKCs, thereby improving MASLD. A3AR expression was significantly elevated in KCs from both patients with MASLD and fast-food diet (FFD)-fed mice. A3AR knockout (KO) mice displayed marked improvements in hepatic inflammation and fibrosis along with a reduction in CLEC4F-positive KCs. The spatial transcriptomics of these KCs revealed disrupted mitochondrial integrity, increased oxidative stress, and enhanced cell death due to A3AR deletion. Similarly, in vivo FM101 treatment, a highly potent and selective antagonist of A3AR with a truncated 4'-thioadenosine structure, mitigated FFD-induced MASLD in mice. Mechanistically, FM101 induces β-arrestin2-mediated A3AR degradation, leading to mitochondrial dysfunction-mediated necroptosis in KCs. Consistently, A3AR was highly expressed in monocyte-derived macrophages in MASLD patients, with strong correlations with macrophage activation and monocyte chemoattractant gene sets. Thus, FM101 induced necroptosis in pro-inflammatory MoKCs, facilitating anti-inflammatory effects. This study demonstrated that inhibiting A3AR via FM101 or genetic deletion alleviates MASLD by inducing mitochondrial dysfunction and subsequent necroptosis in MoKCs, establishing FM101 as a promising therapeutic strategy for MASLD.

논문정보

형식Research article
게재일2024년 12월 (BRIC 등록일 2024-12-30)
연구진국내(교신)+국외 연구진
분야 의약학 > 약리의학

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