Nε-(Carboxymethyl)lysine induces mitochondrial stress, inflammatory activation, and fibrogenic remodelling in multicellular human liver organoids.

Authors

Jin Young Min, Min Ji Gu, Hye Min Kim, Donghwan Kim, Geul Bang, Sang-Yeop Lee, Hae Won Jung, Kwan Soo Hong, Dae Won Jun, Seung Min Lee, Sang Keun Ha, Eun Hee Han

Published in

Pharmacological research. Pages 109653. Sep 28, 2026. Epub Sep 28, 2026.

Abstract

Advanced glycation end-products (AGEs) accumulate in metabolic dysfunction-associated steatotic liver disease (MASLD); however, the contribution of individual AGE species remains poorly defined. We focused on Nε-(carboxymethyl)lysine (CML), a well-characterised AGE generated through glycoxidation and lipid peroxidation, and investigated its association with steatotic liver disease and its effects in multicellular liver models. AGE-RAGE pathway activity was analysed in public liver transcriptomic cohorts, and total AGEs and CML were quantified in human liver and serum. Free CML was then used as a defined experimental stimulus in mice, HepG2 2D/3D, and human induced pluripotent stem cell-derived liver organoid (HLO) models. AGE-RAGE pathway activity was associated with steatohepatitis-related features, whereas hepatic CML was selectively elevated in steatotic liver. Oral CML induced AGE-RAGE- and transforming growth factor beta-associated transcriptional changes in mice but minimal histological fibrosis, whereas HepG2 models showed limited CML-associated lipid accumulation. In contrast, HLOs exhibited concentration-dependent lipid accumulation and fibrogenic remodelling. Single-cell and functional analyses further revealed coordinated mitochondrial stress, inflammatory activation, stellate-cell remodelling, and collagen deposition. Selected responses were attenuated by pathway-targeted interventions, and patient serum cytokine and liver proteomic profiles showed partial concordance with HLO-associated signatures. Together, these findings identify hepatic CML as an AGE-related feature of steatotic liver disease and demonstrate coordinated mitochondrial, inflammatory, and fibrogenic responses to CML in multicellular HLOs. These results support the utility of HLOs for investigating AGE-specific mechanisms in human liver pathology.

PMID:
42805518
Bibliographic data and abstract were imported from PubMed on 29 Sep 2026.

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