AMPK-Directed Therapeutics for MASLD: Mechanistic Rationale, Activator Classes, and Clinical Translation
4 affiliations
- 1College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, 501 Jinju Daero, Jinju 52828, Gyeongnam, Republic of Korea
- 2Phytoeco, Inc., Bldg. B, Room 404, 197 Injero, Gimhae 50834, Gyeongnam, Republic of Korea
- 3Wasong Agricultural Co., Ltd., Bldg. B, Room 403, 197 Injero, Gimhae 50834, Gyeongnam, Republic of Korea
- 4College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, 197 Injero, Gimhae 50834, Gyeongnam, Republic of Korea
Abstract
Metabolic-associated steatotic liver disease (MASLD) affects an estimated 25–30% of the global adult population and represents a leading cause of liver-related morbidity. However, approved pharmacological therapies remain strictly limited. AMP-activated protein kinase (AMPK), a highly conserved heterotrimeric serine/threonine kinase and major regulator of cellular energy homeostasis, is chronically suppressed in the steatotic liver through hyperinsulinemia, ceramide signaling, oxidative stress, and epigenetic silencing of its upstream activator LKB1. This suppression removes a critical brake on de novo lipogenesis while simultaneously impairing fatty acid β-oxidation, mitochondrial quality control, anti-inflammatory signaling, and hepatic stellate cell quiescence. Thus, AMPK restoration may serve as an effective strategy capable of addressing multiple pathological drivers of MASLD. This review examines the molecular architecture of the AMPK heterotrimer, the downstream signaling networks governing hepatic lipid metabolism, glucose homeostasis, and fibrogenesis, and a spectrum of AMPK-activating pharmacology relevant to MASLD. Furthermore, it would introduce indirect activators including metformin, berberine, resveratrol, and related phytochemicals, as well as direct allosteric activators targeting the ADaM site, such as A-769662, PF-06409577, MK-8722, Compound 991, and the clinical-stage compound O304. Translational challenges confronting this therapeutic class are critically evaluated.
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BibTeX
@article{amatya2026ampkdirected,
title = {{AMPK-Directed Therapeutics for MASLD: Mechanistic Rationale, Activator Classes, and Clinical Translation}},
author = {Reeju Amatya and Ji Yeon Hyun and Jun Hak Lee and Kyoung Ah Min and Meong Cheol Shin},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = sep,
doi = {10.3390/ijms27188358},
url = {https://www.mdpi.com/1422-0067/27/18/8358},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - AMPK-Directed Therapeutics for MASLD: Mechanistic Rationale, Activator Classes, and Clinical Translation
AU - Reeju Amatya
AU - Ji Yeon Hyun
AU - Jun Hak Lee
AU - Kyoung Ah Min
AU - Meong Cheol Shin
PY - 2026
DA - 2026/09/19
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27188358
UR - https://www.mdpi.com/1422-0067/27/18/8358
AB - Metabolic-associated steatotic liver disease (MASLD) affects an estimated 25–30% of the global adult population and represents a leading cause of liver-related morbidity. However, approved pharmacological therapies remain strictly limited. AMP-activated protein kinase (AMPK), a highly conserved heterotrimeric serine/threonine kinase and major regulator of cellular energy homeostasis, is chronically suppressed in the steatotic liver through hyperinsulinemia, ceramide signaling, oxidative stress, and epigenetic silencing of its upstream activator LKB1. This suppression removes a critical brake on de novo lipogenesis while simultaneously impairing fatty acid β-oxidation, mitochondrial quality control, anti-inflammatory signaling, and hepatic stellate cell quiescence. Thus, AMPK restoration may serve as an effective strategy capable of addressing multiple pathological drivers of MASLD. This review examines the molecular architecture of the AMPK heterotrimer, the downstream signaling networks governing hepatic lipid metabolism, glucose homeostasis, and fibrogenesis, and a spectrum of AMPK-activating pharmacology relevant to MASLD. Furthermore, it would introduce indirect activators including metformin, berberine, resveratrol, and related phytochemicals, as well as direct allosteric activators targeting the ADaM site, such as A-769662, PF-06409577, MK-8722, Compound 991, and the clinical-stage compound O304. Translational challenges confronting this therapeutic class are critically evaluated.
SN - 1422-0067
ER -