Fructose-related metabolic stress in MASLD: integrating intestinal substrate partitioning, hepatic phosphorus metabolite dynamics, and the inflammatory-fibrotic interface
- 1Graduate School, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
- 2Basic Medical College of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
Abstract
Fructose intake is associated with metabolic dysfunction-associated steatotic liver disease (MASLD), yet similar levels of intake may produce divergent hepatic outcomes. Previous reviews have largely focused on ketohexokinase (KHK)-mediated fructose catabolism, de novo lipogenesis (DNL), uric acid metabolism, or the gut–liver axis, with less attention to the links among intestinal substrate partitioning, dynamic hepatic phosphorus metabolite responses, triacylglycerol (TAG) assembly, and disease stage. This review organizes these pathways within a dual-input, dual-timescale framework to distinguish dietary intake from effective hepatic exposure and acute metabolic responses from chronic disease outcomes, while identifying unvalidated links between these levels. Intact fructose and small-intestine-derived metabolites entering the portal circulation are classified as substrate-related inputs, whereas distal fructose spillover, microbial functional changes, barrier status, and microbe-derived molecules are classified as gut-derived signaling inputs. The framework distinguishes substrate supply relevant to hepatic KHK-fructose−1-phosphate (F1P) processing and TAG assembly from gut-derived signals potentially relevant to the inflammatory context; their independent causal contributions in human MASLD remain unestablished. These inputs may converge at the level of hepatocellular injury and the intrahepatic immune environment, but their covariance and temporal order have not been examined within a unified human study. Human fructose-challenge studies support KHK-dependent phosphomonoester and inorganic phosphate responses as pharmacodynamic readouts. This evidence does not establish comparable KHK dependence across the full adenosine triphosphate (ATP) time course or validate these acute responses as predictors of metabolic dysfunction-associated steatohepatitis (MASH) activity or fibrosis progression. The proposed roles of circulating glycerate, glycerol-3-phosphate (G3P)-free fatty acid (FFA) coupling, and microbial fructose buffering are supported primarily by experimental evidence. By separating fructose exposure, immediate metabolic responses, background amplifiers, and disease outcomes, this framework provides a testable basis for studies combining standardized fructose challenges, phosphorus-31 magnetic resonance spectroscopy (31P-MRS), stable-isotope tracing, and longitudinal disease outcomes.
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BibTeX
@article{qi2026fructoserelated,
title = {{Fructose-related metabolic stress in MASLD: integrating intestinal substrate partitioning, hepatic phosphorus metabolite dynamics, and the inflammatory-fibrotic interface}},
author = {Lin Qi and Yang Du and Yunze Shi and Xingyuan Huang and Mingfeng Liu and Ying Fang and Xiaoyang Hu},
journal = {Frontiers in Medicine},
year = {2026},
month = oct,
doi = {10.3389/fmed.2026.1964793},
url = {https://doi.org/10.3389/fmed.2026.1964793},
note = {CC BY},
}
RIS
TY - JOUR
TI - Fructose-related metabolic stress in MASLD: integrating intestinal substrate partitioning, hepatic phosphorus metabolite dynamics, and the inflammatory-fibrotic interface
AU - Lin Qi
AU - Yang Du
AU - Yunze Shi
AU - Xingyuan Huang
AU - Mingfeng Liu
AU - Ying Fang
AU - Xiaoyang Hu
PY - 2026
DA - 2026/10/28
JO - Frontiers in Medicine
DO - 10.3389/fmed.2026.1964793
UR - https://doi.org/10.3389/fmed.2026.1964793
AB - Fructose intake is associated with metabolic dysfunction-associated steatotic liver disease (MASLD), yet similar levels of intake may produce divergent hepatic outcomes. Previous reviews have largely focused on ketohexokinase (KHK)-mediated fructose catabolism, de novo lipogenesis (DNL), uric acid metabolism, or the gut–liver axis, with less attention to the links among intestinal substrate partitioning, dynamic hepatic phosphorus metabolite responses, triacylglycerol (TAG) assembly, and disease stage. This review organizes these pathways within a dual-input, dual-timescale framework to distinguish dietary intake from effective hepatic exposure and acute metabolic responses from chronic disease outcomes, while identifying unvalidated links between these levels. Intact fructose and small-intestine-derived metabolites entering the portal circulation are classified as substrate-related inputs, whereas distal fructose spillover, microbial functional changes, barrier status, and microbe-derived molecules are classified as gut-derived signaling inputs. The framework distinguishes substrate supply relevant to hepatic KHK-fructose−1-phosphate (F1P) processing and TAG assembly from gut-derived signals potentially relevant to the inflammatory context; their independent causal contributions in human MASLD remain unestablished. These inputs may converge at the level of hepatocellular injury and the intrahepatic immune environment, but their covariance and temporal order have not been examined within a unified human study. Human fructose-challenge studies support KHK-dependent phosphomonoester and inorganic phosphate responses as pharmacodynamic readouts. This evidence does not establish comparable KHK dependence across the full adenosine triphosphate (ATP) time course or validate these acute responses as predictors of metabolic dysfunction-associated steatohepatitis (MASH) activity or fibrosis progression. The proposed roles of circulating glycerate, glycerol-3-phosphate (G3P)-free fatty acid (FFA) coupling, and microbial fructose buffering are supported primarily by experimental evidence. By separating fructose exposure, immediate metabolic responses, background amplifiers, and disease outcomes, this framework provides a testable basis for studies combining standardized fructose challenges, phosphorus-31 magnetic resonance spectroscopy (31P-MRS), stable-isotope tracing, and longitudinal disease outcomes.
SN - 2296-858X
ER -