# Intracellular Oxidant Levels Are Crucial for Cell Survival and JAK/STAT Signaling in Classical Hodgkin’s Lymphoma

## TL;DR

This study shows that oxidants like hydrogen peroxide are essential for the survival and signaling in classical Hodgkin’s lymphoma cells.

## Contribution

The study reveals that oxidant homeostasis is critical for JAK/STAT signaling in classical Hodgkin’s lymphoma.

## Key findings

- Inhibiting oxidants reduces proliferation and induces apoptosis in Hodgkin’s lymphoma cell lines.
- Reduced oxidants correlate with decreased STAT6 activity and DNA binding.
- Maintaining oxidant levels is crucial for JAK/STAT-driven survival in Hodgkin’s lymphoma cells.

## Abstract

Although oxidants are known to be deleterious for cellular homeostasis by oxidizing macromolecules like DNA or proteins, they are also involved in signaling processes essential for cellular proliferation and survival. Here, we investigated the role of superoxide anion (O2−) and hydrogen peroxide (H2O2) homeostasis for the proliferation and survival of classical Hodgkin’s lymphoma (cHL) cell lines. Inhibition of NADPH oxidases (NOX) using apocynin (Apo) and diphenylene iodonium (DPI), or treatment with the antioxidant butylated hydroxyanisole (BHA), significantly reduced proliferation and induced apoptosis in HL cell lines. These effects correlated with transcriptomic alterations involving redox regulation, immune signaling, and cell cycle control. Interestingly, treatment with DPI or antioxidants attenuated constitutive Signal Transducer and Activator of Transcription (STAT) activity, as seen by decreased phospho-STAT6 levels and reduced STAT6 DNA binding. This suggests a sensitivity of the Janus kinase (JAK)/STAT pathway in cHL cell lines to O2− and H2O2 depletion. Functional assays confirmed this by demonstrating partial restoration of proliferation or apoptosis in L428 cells that expressed constitutively active STAT6 or were transfected with small interfering RNAs (siRNAs) that targeted STAT regulators. These findings highlight that oxidants, particularly H2O2, act as both general oxidative stressors and essential modulators of oncogenic signaling pathways. Specifically, maintenance of oxidant homeostasis is critical for sustaining JAK/STAT-mediated growth and survival programs in cHL cells. Targeting redox homeostasis might offer a promising therapeutic strategy to impair JAK/STAT-driven proliferation and survival in cHL.