Belumosudil-associated neurological adverse events: evidence from FAERS and experimental validation

Belumosudil, a first-in-class ROCK2 inhibitor, was approved by the U.S. Food and Drug Administration in 2021 for the treatment of chronic graft-versus-host disease (cGVHD). This study aimed to evaluate the real-world safety profile of belumosudil and investigate its potential neurological adverse effects (AEs).

Adverse events (AEs) related to belumosudil were extracted from the FDA Adverse Event Reporting System (FAERS) from Q3 2021 to Q2 2025. Signal detection was performed using four disproportionality methods: reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS). Time-to-onset was analyzed using the Weibull distribution. Network pharmacology analysis, including target prediction, disease-gene collection, protein-protein interaction network construction, and GO/KEGG enrichment analyses, was conducted to explore potential targets and pathways associated with neurotoxicity. Cellular experiments in SH-SY5Y cells and primary neurons were performed to validate the predicted neurotoxic effects.

A total of 2225 cases involving belumosudil were identified, comprising 5852 AE reports. In addition to known label-listed AEs such as fatigue, nausea, infection, pneumonia, and rash, several potential unlisted AEs were detected, including stomatitis, dry eye, cataract, and neurological events such as neuropathy peripheral, depressed mood, and emotional disorder. The median onset time was 78.5 days (IQR 23-169.5), with most events occurring within the first 30 days. Network pharmacology identified 46 overlapping targets, and enrichment analysis highlighted pathways related to neuronal function and survival. Furthermore, in vitro experiments demonstrated that belumosudil induced dose-dependent neuronal injury in SH-SY5Y cells and impaired neurite outgrowth in primary neurons, which may involve modulation of the AKT signaling pathway.

This study provides a real-world safety evaluation of belumosudil and identifies potential unlisted neurological AEs. Integration of network pharmacology and neuronal experiments provides preliminary support for the potential biological relevance of these findings and highlights the need for further monitoring of neurological AEs.