A3AR antagonism mitigates metabolic dysfunction-associated steatotic liver disease by exploiting monocyte-derived Kupffer cell necroptosis and inflammation resolution

  • Metabolism. 2025 Mar:164:156114. doi: 10.1016/j.metabol.2024.156114.
Jeong-Su Park  1 ,  Yuan-Qiang Ma  1 ,  Feng Wang  1 ,  Hwan Ma  1 ,  Guoyan Sui  1 ,  Nodir Rustamov  1 ,  Minyeong Han  1 ,  Yejin Son  1 ,  Chun-Woong Park  1 ,  Sang-Bae Han  1 ,  Jin Tae Hong  1 ,  Lak Shin Jeong  2 ,  Jin Lee  3 ,  Yoon Seok Roh  4
Affiliations
  • 1. College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, South Korea.
  • 2. Research and Development Center, Future Medicine Co., Ltd, Seongnam, South Korea; College of Pharmacy, Seoul National University, Seoul, South Korea.
  • 3. Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: [email protected].
  • 4. College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, South Korea. Electronic address: [email protected].
PMID: 39732364 DOI: 10.1016/j.metabol.2024.156114
Abstract

Background & aims: 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.

Approach & results: 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.

Conclusions: 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.

Keywords
A3AR; GPCR; Kupffer cells death; MASLD; Necroptosis; β-arrestin2.
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