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. 2025 Aug;19(4):836-845.
doi: 10.1007/s12072-025-10800-y. Epub 2025 Mar 14.

Efficacy of measuring natural killer-activating receptor ligands to predict the pathogenesis of metabolic dysfunction-associated steatotic liver disease

Jun Arai  1 , Akinori Okumura  2 , Satoshi Kimoto  3 , Kazumasa Sakamoto  3 , Tomoya Kitada  3 , Rena Kitano  3 , Tadahisa Inoue  3 , Sayaka Nishimura  3 , Noriko Inden  3 , Yukiko Muraki  3 , Naoya Kato  4 , Kiyoaki Ito  3
Affiliations

Efficacy of measuring natural killer-activating receptor ligands to predict the pathogenesis of metabolic dysfunction-associated steatotic liver disease

Jun Arai et al. Hepatol Int. 2025 Aug.

Abstract

Objective: The proportion of non-B/non-C hepatocellular carcinoma cases is increasing, and the principal cause is metabolic dysfunction-associated steatotic liver disease (MASLD). The degree of intrahepatic natural killer (NK) cell infiltration has been reported to correlate with MASLD progression. However, reports on MASLD are limited. We aimed to investigate the involvement of NK cell-activating receptor ligands in MASLD pathogenesis.

Methods: This study cohort comprised 69 patients with biopsy-proven MASLD treated between 2012 and 2018 at our institute. The concentrations of major histocompatibility complex class I polypeptide-related sequences A and B (MICA and MICB, respectively) and B7H6 in patient sera were measured using enzyme-linked immunosorbent assay kits. Data were statistically compared between those with metabolic-associated steatotic liver (MASL, n = 25) and those with metabolic dysfunction-associated steatohepatitis (MASH, n = 44). The clinical characteristics related to higher concentrations of each NK cell-activating receptor ligand were also investigated.

Results: The MASH group had a higher level of the ligands than the MASL group. Furthermore, the MASH group had a significantly higher level of the Mac-2-binding protein glycosylation isomer (M2BPGi) than the MASL group (p < 0.001). MICA and MICB were positively correlated, and all three ligands were strongly correlated with alpha-fetoprotein and protein induced by vitamin K absence 2. Although MICB levels positively correlated with aspartate transaminase and alanine transaminase levels (p < 0.005), patients with higher MICA and B7H6 levels had higher M2BPGi levels. Interestingly, concentrations of B7H6 were significantly correlated with portal inflammation (p < 0.001), rather than lobular inflammation.

Conclusion: The three NK-activating receptor ligands were higher in the sera of the MASH group than those of the MASL group and strongly correlated with tumor markers, indicating the potential for hepatocarcinogenesis. Higher concentrations of serum B7H6 were correlated with advanced fibrosis and the degree of portal inflammation, which is a potential biomarker for predicting the pathogenesis of MASH.

Keywords: B7H6, MICA; MASH; MASLD; MICB; NK cell.

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Conflict of interest statement

Declarations. Conflict of interest: The authors declare that they have no conflicts of interest regarding this article. Ethical approval: This research project was approved by a suitably constituted Ethics Committee of our institution, and it confirmed that the project was in accordance with the provisions of the Declaration of Helsinki. This research was approved by the ethical committees of the Aichi Medical University Hospital. Informed consent: Written informed consent was obtained from each participant.

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