# HMOX1 drives dihydroartemisinin-sensitized ferroptosis antagonized by mitochondrial fusion

## TL;DR

The study shows how dihydroartemisinin increases cell sensitivity to ferroptosis, a type of cell death, through HMOX1 and mitochondrial fusion.

## Contribution

The novel finding is that DHA activates HMOX1 to trigger mitochondrial fusion, which suppresses ferroptosis.

## Key findings

- Non-lethal doses of DHA sensitize cells to GPX4-dependent ferroptosis.
- DHA activates HMOX-1, forming a feedback loop that drives mitochondrial fusion via Mfn1/2.
- Low Mfn2 levels may correlate with longer overall survival in sarcoma and thymoma patients.

## Abstract

Artemisinin is the key component of artemisinin-based combination therapy (ACT) for malaria. Combinations of artemisinin with partner drugs demonstrate significant therapeutic potential in various diseases, including cancer. However, the precise mechanisms by which artemisinin, in combination with partner drugs, induces cell death are still not fully understood. Ferroptosis, a distinct form of cell death characterized by its dependence on iron, oxygen, and phospholipids (PLs), represents one potential pathway. In this study, we discovered that dihydroartemisinin (DHA), the active metabolite of artemisinin and its derivatives, sensitizes cells to ferroptosis induced by GPX4 inhibition. Through integrated data analysis and experimental validation, we found that DHA enhances ferroptosis sensitivity by promoting heme oxygenase 1 (HMOX1, HO-1)-mediated mitochondrial oxidative stress, thereby triggering a feedback loop that promotes mitochondrial fusion. These results broaden our understanding of the mechanisms of DHA in combination with partner drugs, and provide insights for clinical translation of ferroptosis.

•Non-lethal doses of DHA sensitize cells to GPX4-dependent ferroptosis•DHA activates HMOX-1, forming a feedback loop that drives mitochondrial fusion via Mfn1/2•Mitochondrial fusion acts as a suppressor of ferroptosis•Low Mfn2 levels may correlate with longer overall survival in sarcoma and thymoma patients

Non-lethal doses of DHA sensitize cells to GPX4-dependent ferroptosis

DHA activates HMOX-1, forming a feedback loop that drives mitochondrial fusion via Mfn1/2

Mitochondrial fusion acts as a suppressor of ferroptosis

Low Mfn2 levels may correlate with longer overall survival in sarcoma and thymoma patients

Drug delivery system; Drug dispensing; Pharmacology; Therapeutics