Bifendate inhibits cell PARthanatos by activating the MEK/ERK pathway.

PARthanatos is a form of programmed cell death increasingly implicated in neurodegenerative diseases and ischemic stroke. Although classical PARP-1 inhibitors can interrupt this pathway, their prolonged use carries a risk of genomic instability. Screening an NMPA-approved compound library identified compound Bifendate (DDB), a clinical used anti-hepatitis drug, as a effective PARthanatos suppressor. In HeLa and SH-SY5Y cells exposed to the PARthanatos inducer MNNG, DDB increased cell viability by approximately 30 % and 70 %, respectively. This inhibitory effect was not attributable to altered protein levels of PARP-1, AIF, or MIF, but to the blockade of AIF translocation from mitochondria to the cytoplasm and nucleus. Mechanistic analyses revealed that DDB treatment can significantly activate MEK, ERK and then phosphorylate Bad. This activation helps to maintain the mitochondrial membrane potential and permeability, and prevent the release of AIF, and thereby blocks the PARthanatos cascade downstream of PARP-1 activation. Unlike PARP-1 inhibitors, DDB does not interfere with PARP-1 enzymatic activity. Instead, DDB exerts its effects by modulating ERK signaling and enhancing ERK activation. Collectively, these findings provide novel insights into the development of neuroprotective drugs that inhibit PARthanatos without compromising PARP-1 function, highlighting DDB as a promising therapeutic candidate for neurological disorders.