Hyperactivation of β-catenin rewires mitochondrial fuel selection in liver cancer cells
Abstract
Metabolic state is tightly linked to cell fate, and expression of the mitochondrial pyruvate carrier (MPC), which imports pyruvate into mitochondria, is a robust marker of it. The transcriptional regulators that set metabolic state, however, remain poorly defined. In the liver, {beta}-catenin is one of the determinants of metabolic zonation, and activating CTNNB1 mutations are frequent in hepatocellular carcinoma. Here we show that {beta}-catenin regulates metabolic state in liver cancer cells. An unbiased CRISPR screen that uses endogenous MPC1 transcript abundance as the marker identifies CTNNB1. Activating {beta}-catenin pharmacologically or genetically reduces MPC1 and MPC2 transcript and protein levels, and MPC expression is also low in {beta}-catenin-driven liver tumors in vivo. Beyond the MPC, {beta}-catenin activation impairs assembly of respiratory Complexes III and IV, reduces mitochondrial DNA content and respiratory capacity, elongates mitochondrial networks and remodels the lipidome. Stable isotope tracing shows reduced entry of glucose- and lactate-derived carbon into the TCA cycle alongside increased oxidation of palmitate and oleate. These findings identify {beta}-catenin as a regulator of metabolic state that drives a fuel switch from carbohydrate to fatty acid oxidation in liver cancer cells.
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BibTeX
@misc{cedenorosario2026hyperactivation,
title = {{Hyperactivation of β-catenin rewires mitochondrial fuel selection in liver cancer cells}},
author = {Luis Cedeño-Rosario and Queren A. Alcantara and Nicole A. Sierra and Praveena Prasad and Jillian Wright and Geanette Lam and Nimo Abdi and Jaide Florence and Alex J. Bott and Katarina Heyden and Joshua C. Youngs and Álvaro J. Narbona-Pérez and Lorenzo Gastelum Mena and Monika A. Makurath and Jesse N. Velasco-Silva and Mi-Young Jeong and Sarah Fogarty and Gregory S. Ducker and Jennifer Lippincott-Schwartz and Melanie R. McReynolds and Jared Rutter},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.18.759986},
url = {https://www.biorxiv.org/content/10.64898/2026.10.18.759986v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Hyperactivation of β-catenin rewires mitochondrial fuel selection in liver cancer cells
AU - Luis Cedeño-Rosario
AU - Queren A. Alcantara
AU - Nicole A. Sierra
AU - Praveena Prasad
AU - Jillian Wright
AU - Geanette Lam
AU - Nimo Abdi
AU - Jaide Florence
AU - Alex J. Bott
AU - Katarina Heyden
AU - Joshua C. Youngs
AU - Álvaro J. Narbona-Pérez
AU - Lorenzo Gastelum Mena
AU - Monika A. Makurath
AU - Jesse N. Velasco-Silva
AU - Mi-Young Jeong
AU - Sarah Fogarty
AU - Gregory S. Ducker
AU - Jennifer Lippincott-Schwartz
AU - Melanie R. McReynolds
AU - Jared Rutter
PY - 2026
DA - 2026/10/18
PB - bioRxiv
DO - 10.64898/2026.10.18.759986
UR - https://www.biorxiv.org/content/10.64898/2026.10.18.759986v1
AB - Metabolic state is tightly linked to cell fate, and expression of the mitochondrial pyruvate carrier (MPC), which imports pyruvate into mitochondria, is a robust marker of it. The transcriptional regulators that set metabolic state, however, remain poorly defined. In the liver, {beta}-catenin is one of the determinants of metabolic zonation, and activating CTNNB1 mutations are frequent in hepatocellular carcinoma. Here we show that {beta}-catenin regulates metabolic state in liver cancer cells. An unbiased CRISPR screen that uses endogenous MPC1 transcript abundance as the marker identifies CTNNB1. Activating {beta}-catenin pharmacologically or genetically reduces MPC1 and MPC2 transcript and protein levels, and MPC expression is also low in {beta}-catenin-driven liver tumors in vivo. Beyond the MPC, {beta}-catenin activation impairs assembly of respiratory Complexes III and IV, reduces mitochondrial DNA content and respiratory capacity, elongates mitochondrial networks and remodels the lipidome. Stable isotope tracing shows reduced entry of glucose- and lactate-derived carbon into the TCA cycle alongside increased oxidation of palmitate and oleate. These findings identify {beta}-catenin as a regulator of metabolic state that drives a fuel switch from carbohydrate to fatty acid oxidation in liver cancer cells.
SN - 2692-8205
ER -