Screening of orthopedic medicines identifies raloxifene hydrochloride as a novel ferroptosis inhibitor for spinal cord injury therapy

Abstract

Spinal cord injury (SCI) is a severe condition that can lead to irreversible central nervous system damage. Spinal cord injury patients frequently present with coexisting orthopedic conditions, and many of them also have underlying bone and joint diseases. Recent studies have identified ferroptosis as a significant contributor that exacerbates the progression of spinal cord injury. This study conducted a screening in common orthopedic medications, which includes anti-osteoporosis agents and calcium supplements, in order to identify potential ferroptosis inhibitors and investigate their therapeutic effects on spinal cord injury. Among the 8 drugs screened, raloxifene hydrochloride was found to significantly inhibit ferroptosis induced by RSL3 in neural cells. Subsequent studies confirmed its inhibitory effect on ferroptosis both in vitro and in vivo. It was also demonstrated that Nrf2 inhibitor Brusatol could reverse the anti-ferroptotic effect of Raloxifene hydrochloride in neural cells in vitro as well as its therapeutic effect on SCI in vivo, suggesting its inhibitory effect on ferroptosis is through Nrf2. This study identifies a novel ferroptosis inhibitor among orthopedic medicines and also confirms the therapeutic effect of Raloxifene hydrochloride on SCI. The results of the current study may provide reference for the clinical administration of SCI.