Maackiain Suppresses Hepatocellular Carcinoma by Restoring ESR1-Dependent Mitochondrial Function
Year: 2026
Type: article
Abstract: Objective: To investigate the antitumor effects of maackiain (MAA), a naturally occurring pterocarpan found in Sophora flavescens, and clarify its molecular mechanism in hepatocellular carcinoma (HCC). Methods: Network pharmacology was integrated with transcriptomic analyses of three independent HCC cohorts. GSE334651 served as the discovery cohort, whereas GSE251942 and The Cancer Genome Atlas Liver Hepatocellular Carcinoma project (TCGA-LIHC) were used for validation. Candidate targets were prioritized using expression, diagnostic, clinicopathological, and survival analyses. Molecular docking assessed the predicted interaction between MAA and estrogen receptor alpha (ERα), encoded by estrogen receptor 1 (ESR1). MAA was evaluated in Huh7 and HepG2 cells using viability, migration, invasion, gene-expression, and mitochondrial-function assays. ESR1 involvement was examined using small interfering RNA (siRNA) in vitro and stable short hairpin RNA (shRNA) knockdown in Huh7 xenografts. Results: Among 12,017 commonly evaluable protein-coding genes, 514 robust HCC-associated differentially expressed genes were identified. Intersection with 14 MAA-associated targets yielded four candidates, and ESR1 was prioritized. MAA increased ESR1 expression and inhibited HCC cell viability, migration, and invasion. At 40 μM, MAA increased mitochondrial membrane potential, oxygen consumption, and adenosine triphosphate (ATP) content and reduced reactive oxygen species (ROS) levels. ESR1 knockdown attenuated several bioenergetic and antitumor responses, although ROS reduction remained detectable. In vivo, MAA inhibited xenograft growth and increased ESR1, ATP5A, and NDUFB8 protein abundance and intratumoral ATP content; these responses were weaker in ESR1-depleted tumors. Conclusions: MAA suppresses HCC progression in association with increased ESR1 expression and improved mitochondrial function. The loss-of-function findings support a contribution from ESR1 and warrant further evaluation of target specificity and mitochondrial causality.
Source: Biomedicines
Authors: Gong Chen, Qin Sun, Ximing Xu
Institution: Renmin Hospital of Wuhan University
Language: English
Topic: Bioactive natural compounds
Subfield: Drug Discovery
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,137
OpenAlex ID: W7225661500