# ALDH1L2 induces resistance to chemotherapy in small cell lung cancer by inhibiting ferroptosis

## TL;DR

This study shows that ALDH1L2 helps small cell lung cancer resist chemotherapy by preventing a type of cell death called ferroptosis, and combining thiostrepton with chemotherapy could improve treatment outcomes.

## Contribution

The study identifies ALDH1L2 as a novel driver of chemoresistance in SCLC through its role in inhibiting ferroptosis and proposes thiostrepton as a potential therapeutic strategy.

## Key findings

- ALDH1L2 expression is a poor prognostic factor for SCLC patients.
- ALDH1L2 inhibits ferroptosis by reducing lipid peroxidation and interacting with the TRX2-PRDX3 antioxidant network.
- Thiostrepton synergizes with chemotherapy to suppress SCLC tumor growth.

## Abstract

Small cell lung cancer (SCLC) is known for its rapid growth and early metastasis, and SCLC patients are highly susceptible to chemoresistance. Studies have shown that the combination of ferroptosis induction and TRX pathway inhibition can significantly inhibit SCLC tumor growth, but the molecular mechanisms underlying ferroptosis in SCLC are poorly understood. In this study, we explored the regulatory role of the ALDH1L2-related metabolic pathway in SCLC chemoresistance by machine learning. We found that ALDH1L2 expression is a poor prognostic factor for SCLC patients and that high ALDH1L2 expression can negatively regulate the level of cellular lipid peroxidation and inhibit ferroptosis, thereby promoting SCLC chemoresistance. Mechanistically, ALDH1L2 interacts with the TRX2-PRDX3 antioxidant network to reduce the levels of hyperoxidized PRDX3 and oxidized PRDX3 dimers in the plasma membrane under cisplatin-induced stress and decrease cellular susceptibility to ferroptosis, thus promoting SCLC chemoresistance. In addition, we found that thiostrepton, a PRDX3 inhibitor, can synergize with chemotherapy to suppress tumor growth in SCLC, suggesting that thiostrepton might be a promising new tool for overcoming SCLC chemoresistance.

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•ALDH1L2 is a poor prognostic factor and promotes SCLC chemoresistance.•ALDH1L2 can reduce the level of cellular lipid peroxidation and inhibit ferroptosis, thus contributing to SCLC chemoresistance.•ALDH1L2 can interact with the TRX2-PRDX3 antioxidant network and reduce the levels of hyperoxidized PRDX3 and oxidized PRDX3 dimers in the plasma membrane under cisplatin-induced stress, decreasing susceptibility to ferroptosis and promoting SCLC chemoresistance.•The combination of chemotherapy and thiostrepton, a PRDX3 inhibitor, exerts synergistic therapeutic effects against SCLC in vivo.

ALDH1L2 is a poor prognostic factor and promotes SCLC chemoresistance.

ALDH1L2 can reduce the level of cellular lipid peroxidation and inhibit ferroptosis, thus contributing to SCLC chemoresistance.

ALDH1L2 can interact with the TRX2-PRDX3 antioxidant network and reduce the levels of hyperoxidized PRDX3 and oxidized PRDX3 dimers in the plasma membrane under cisplatin-induced stress, decreasing susceptibility to ferroptosis and promoting SCLC chemoresistance.

The combination of chemotherapy and thiostrepton, a PRDX3 inhibitor, exerts synergistic therapeutic effects against SCLC in vivo.