# Okanin Suppresses the Growth of Colorectal Cancer Cells by Targeting at Peroxiredoxin 5

## TL;DR

Okanin, a natural compound, fights colorectal cancer by targeting PRDX5, causing cell death through apoptosis and ferroptosis.

## Contribution

Okanin's novel mechanism of targeting PRDX5 to induce cancer cell death via a new PRDX5/GPX4/SIAH2/WSB1 signaling axis is revealed.

## Key findings

- Okanin selectively inhibits colorectal cancer cell growth with minimal impact on non-cancerous cells.
- Okanin binds PRDX5, inhibits its activity, and triggers ROS production and cell death via apoptosis and ferroptosis.
- Okanin's anti-cancer effects are compromised in PRDX5-overexpressing cells, confirming PRDX5 as a key target.

## Abstract

Okanin is a natural product with few known biological activities. Its anti‐cancer effects and the underlying mechanisms are investigated. It is found that okanin inhibits cancer cell growth (25–50 µm) with minimal effects on non‐cancerous colorectal cells except at much higher doses (i.e., > 100 µm). In colorectal HCT116 cancer cells, okanin binds directly to peroxiredoxin 5 (PRDX5) at a site opposite the catalytic domain, which directly inhibits the enzymatic activity and triggers the production of reactive oxygen species, leading to independent apoptosis and ferroptosis. The binding also causes WSB1‐mediated ubiquitination degradation of PRDX5, resulting in reduced transcription and SIAH2‐mediated ubiquitination degradation of GPX4, which similarly causes apoptosis and ferroptosis. In xenograft mouse models, okanin decreases the PRDX5 level and inhibits the growth of HCT116 cells, both of which are compromised when cells stably overexpressing PRDX5 are used. Okanin does not change the body weight of the animals; in comparison, 5‐fluorouracil reduces the body weight, despite being less effective. In conclusion, the results suggest that okanin targets PRDX5, which capacitates it for anti‐cancer activity via apoptosis and ferroptosis independently. Okanin is a promising investigational drug. PRDX5 and GPX4 are candidate targets for cancer chemotherapy, at least for colorectal cancer.

Okanin suppresses colorectal cancer growth by directly targeting PRDX5. This natural compound selectively binds peroxiredoxin 5 (PRDX5), inhibiting its activity and inducing WSB1‐mediated degradation. PRDX5 loss elevates ROS, suppresses GPX4 via SIAH2, and further triggers cell death (apoptosis and ferroptosis). The results unveil a novel PRDX5/GPX4/SIAH2/WSB1 signaling axis as a promising therapeutic vulnerability for cancer.