Identification of a group of bisbenzylisoquinoline (BBIQ) compounds as ferroptosis inhibitors

Abstract

Ferroptosis induced by detrimental accumulation of lipid peroxides has been recently linked to a variety of pathological conditions ranging from acute tissue injuries to chronic degenerative diseases and suppression of ferroptosis by small chemical inhibitors is beneficial to the prevention and treatment of these diseases. However, in vivo applicable small chemical ferroptosis inhibitors are limited currently. In this study, we screened an alkaloid natural compound library for compounds that can inhibit RSL3-induced ferroptosis in HT1080 cells and identified a group of bisbenzylisoquinoline (BBIQ) compounds as novel ferroptosis-specific inhibitors. These BBIQ compounds are structurally different from known ferroptosis inhibitors and they do not appear to regulate iron homeostasis or lipid ROS generation pathways, while they are able to scavenge 1,1-diphenyl-2-picryl-hydrazyl (DPPH) in cell-free reactions and prevent accumulation of lipid peroxides in living cells. These BBIQ compounds demonstrate good in vivo activities as they effectively protect mice from folic acid-induced renal tubular ferroptosis and acute kidney injury. Several BBIQ compounds are approved drugs in Japan and China for traditional uses and cepharanthine is currently in clinical trials against SARS-CoV-2, our discovery of BBIQs as in vivo applicable ferroptosis inhibitors will expand their usage to prevent ferroptotic tissue damages under various pathological conditions.

Chemical screen in zebrafish lateral line identified compounds that ameliorate neomycin-induced ototoxicity by inhibiting ferroptosis pathway

“…We noticed that five of them (berbamine, cepharanthine, fangchinoline, liensinine and isoliensinine) belong to the bisbenzylisoquinoline (BBIQ) compounds that we recently identified as RTAs and ferroptosis inhibitors [ 44 ]. Consistent with our previous studies, we found these BBIQ compounds effectively block RSL3-induced ferroptosis in HT1080 cells (Fig.…”

“…We identified nine otoprotective compounds from this screen and two of them function to block neomycin uptake and seven of them inhibit ferroptosis, supporting an otoprotective function upon ferroptosis inhibition. Among the seven ferroptosis inhibiting compounds, berbamine, cepharanthine, fangchinoline, liensinine and isoliensinine are BBIQ compounds that were recently identified as ferroptosis inhibitors in our cell-based screen [ 44 ]. Catharanthine does not contain the chemical backbone of BBIQ compounds, but it also has ROS scavenging activity (Fig.…”

“…These data indicate that a compound’s ferroptosis inhibiting activity in zebrafish hair cells largely predicts its activity in cell-based assay. Meanwhile, 15 out of the top 20 hits from our cell-based screen [ 44 ] are not otoprotective in vivo in neomycin-induced hair cell death assay, indicating ferroptosis inhibiting activity in cell-based assay does not guarantee otoprotective function in vivo, possibly due to factors such as compound stability, absorption, distribution, metabolism, toxicity, etc. Thus, positive hits from cell-based screen should be further validated in vivo in models such as zebrafish or mouse for their potential as candidate compounds for further drug development.…”

Curcumin–polydopamine nanoparticles alleviate ferroptosis by iron chelation and inhibition of oxidative stress damage

“…11 Ferroptosis inhibitors, primarily radical-trapping antioxidants and iron chelators, aim to mitigate OS and safeguard cells. 12,13 However, there are signicant hurdles in the initial generation of these compounds in clinical advancement due to off-target effects, limited selectivity, and potential toxicity. 14 Iron chelators, such as deferoxamine, are hindered by poor absorption and rapid clearance.…”