# Mitochondrial Calcium Uniporter Drives Chemoresistance in Pancreatic Cancer via Glutathione‐Mediated Stemness Maintenance

## TL;DR

This study shows that a protein called MCU helps pancreatic cancer resist chemotherapy by boosting stem cell traits, and blocking MCU could improve treatment outcomes.

## Contribution

The study identifies MCU as a driver of chemoresistance in pancreatic cancer through glutathione-mediated stemness maintenance and proposes MCU inhibition as a novel therapeutic strategy.

## Key findings

- MCU upregulation correlates with chemoresistance and stemness in pancreatic cancer.
- MCU inhibition disrupts glutathione synthesis and restores chemotherapy sensitivity.
- The MCU inhibitor NB-598 synergizes with chemotherapy to suppress tumor growth in preclinical models.

## Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with poor prognosis due to chemoresistance. Using integrative single‐cell RNA sequencing, we identified that the upregulation of mitochondrial calcium uniporter (MCU) may contribute to chemoresistance and stemness maintenance in PDAC. MCU was highly expressed in chemotherapy‐resistant PDAC tumors and correlated with enhanced cancer stem cell properties. Mechanistically, MCU‐mediated mitochondrial Ca2+ influx triggered endoplasmic reticulum (ER) stress and the downstream PERK‐eIF2α pathway. This cascade activated ATF4 and NRF2, which enhanced the transcriptional regulation of PSAT1 and SLC7A11. These changes promoted de novo glutathione (GSH) synthesis to scavenge reactive oxygen species (ROS) and sustain stemness. Genetic knockdown or pharmacological inhibition of MCU disrupted GSH synthesis, suppressed stemness, and restored sensitivity to nab‐paclitaxel plus gemcitabine (AG). High‐throughput screening identified MCU inhibitor NB‐598, which synergized with AG to inhibit tumor growth in preclinical models. These findings offer a potential novel therapeutic strategy to address chemoresistance in PDAC.

PDAC has a poor prognosis due to chemoresistance. We revealed that MCU upregulation is associated with chemoresistance and stemness in PDAC. MCU‐mediated Ca2
+ influx induced ER stress, activating the PERK‐ATF4/NRF2 axis to enhance PSAT1/SLC711 expression and glutathione synthesis, reducing ROS and maintaining stemness. The newly identified MCU inhibitor NB‐598 suppressed MCU‐mediated stemness and restored sensitivity to AG chemotherapy.