Work

Targeting FBXO48 with BC1618 promotes axon regeneration and alleviates symptoms of Parkinson’s disease

Year: 2026

Type: article

Abstract: Introduction Neurons depend on the ubiquitin system to maintain proteostasis, which plays crucial roles in processes of neuronal death and axon regeneration after injuries and diseases. Developing druggable targets within the ubiquitin system that simultaneously support neuroprotection and axon regeneration has been considered an attractive therapeutic strategy. Objectives To systematically identify druggable molecules within the ubiquitin signaling pathway and evaluate their efficacy in neuroprotection. Methods To this end, we screened 181 ubiquitination-related small-molecule compounds for neuroprotective effects by performing excitotoxic interventions in HT22 cell lines and mouse primary neurons. Subsequently, using a mouse optic nerve crush model, we demonstrated the neuroprotective effect of BC1618 through RGC survival and axon regeneration. To investigate the mechanism, we employed LC-MS, co-IP, and RNA-seq to delineate the BC1618-FBXO48-SERBP1 regulatory axis and its downstream regulation of mRNA expression. To further evaluate the translational potential of BC1618, we assessed cell survival rates and behavioral impairments using both MPTP-induced mouse Parkinson’s disease model and MPP + -induced apoptosis model of iPSC-derived dopaminergic neurons. Results We identified BC1618 as an effective neuroprotectant that prevented glutamate-induced excitotoxicity in vitro and enhanced neurite outgrowth in immature neurons. Additionally, we showed its effectiveness in an optic nerve crush model, where BC1618 supported RGC survival and encouraged axon regeneration. Mechanistically, BC1618 inhibited FBXO48-mediated K63-linked ubiquitination of SERBP1 at K52, which protected SERBP1 from autophagic degradation. Our findings established SERBP1 as a key regulator that coordinates downstream mRNA expression to mediate neuroprotection. Notably, our results demonstrated that BC1618 mitigated MPTP-induced degeneration of dopaminergic neurons and motor deficits, while also exhibiting robust neuroprotective effects in MPP + -stimulated human-derived dopaminergic neurons. Conclusions These findings highlight that targeting FBXO48 with BC1618 promotes axon regeneration and alleviates symptoms of Parkinson’s disease by reducing the degradation of SERBP1, revealing a novel therapeutic target for clinical translation.

Source: Journal of Advanced Research

DOI: 10.1016/j.jare.2026.07.048