Formononetin ameliorates oxaliplatin-induced peripheral neuropathy via the KEAP1-NRF2-GSTP1 axis

Area of Science:

• Neuroscience
• Pharmacology
• Oncology

Background:

• Oxaliplatin-induced peripheral neuropathy (OIPN) management is challenging due to concerns about reduced chemotherapy efficacy and failure to reverse neuronal damage.
• Targeting redox signaling pathways, particularly the nuclear factor erythroid-2 related factor 2 (NRF2) pathway, shows promise for OIPN therapy.
• Previous research demonstrated the protective role of NRF2 in OIPN.

Purpose of the Study:

• To investigate the protective properties of formononetin (FN) in oxaliplatin-induced peripheral neuropathy (OIPN).
• To elucidate the mechanism by which FN exerts its protective effects against OIPN.
• To assess whether FN impacts the chemotherapeutic function of oxaliplatin.

Main Methods:

• RNA interference experiments to confirm FN's direct activation of the NRF2 pathway.
• Expression profile sequencing to identify FN's downstream targets, including GSTP1.
• Bio-FN synthesis and target protein screening to identify FN's binding site on KEAP1.
• In vivo experiments in mice to evaluate FN's effect on OIPN-related nociceptive sensations.

Main Results:

• Formononetin (FN) was found to protect against OIPN through direct activation of the NRF2 pathway.
• FN exerts its protective effect via the NRF2 downstream enzyme, glutathione S-transferase P1 (GSTP1).
• FN selectively binds to His129 and Lys131 in the BTB domain of KEAP1, a key regulator of NRF2.
• In vivo studies showed that FN-induced NRF2 activation alleviated nociceptive sensations in mice.
• FN did not interfere with oxaliplatin's chemotherapeutic function in colorectal cell lines.

Conclusions:

• Formononetin (FN) represents a novel therapeutic strategy for preventing or attenuating oxaliplatin-induced peripheral neuropathy (OIPN).
• The findings highlight a new binding mechanism between KEAP1 and isoflavones for NRF2 system activation.
• Pharmacological activation of the NRF2-GSTP1 axis offers a promising approach for managing OIPN without compromising cancer treatment efficacy.