Aspartame drives the continuous progression from MASLD to HCC.

Area of Science:

• Hepatology
• Toxicology
• Oncology

Background:

• Aspartame (APM) is a common sweetener linked to cancer.
• Its molecular mechanisms in metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC) are unclear.

Purpose of the Study:

• To elucidate the molecular mechanisms by which APM influences MASLD and HCC.
• To identify key genes and pathways involved in APM-induced hepatocarcinogenesis.

Main Methods:

• Integrated network toxicology, bulk RNA-seq, and molecular docking.
• Analyzed gene expression data from MASLD and HCC patient cohorts.
• Utilized WGCNA, machine learning, and pathway enrichment analyses.

Main Results:

• Identified 12 core genes common to APM exposure, MASLD, and HCC.
• Revealed a "dual-track" mechanism involving suppressed bile-acid export, lipid accumulation, and chronic inflammation (Track A).
• Demonstrated APM hijacking of signaling pathways (p53, nuclear receptors) and identified EGR1 and PTGS2 as key diagnostic genes with high-affinity APM binding.

Conclusions:

• EGR1 and PTGS2 are critical mediators of APM-induced MASLD progression to HCC.
• Proposed a "dual-track" oncogenic model where APM initiates malignant programming via specific gene networks.
• Findings offer mechanistic insights, nominate biomarkers, and suggest therapeutic targets for APM-related liver cancer.