# The Natural Triterpenoid Alisol B Overcomes Temozolomide Resistance in Glioblastoma Through Multi-Target Mechanisms: Coordinated Epigenetic, Metabolic, and Cell-Cycle Reprogramming

## TL;DR

Alisol B, a natural compound, overcomes drug resistance in brain tumors by targeting multiple cellular processes at once.

## Contribution

The study reveals Alisol B's novel multi-target mechanisms in overcoming glioblastoma resistance through epigenetic, metabolic, and cell-cycle changes.

## Key findings

- Alisol B induces endoplasmic reticulum stress and G2/M cell-cycle arrest via lysine acetylation reprogramming.
- It disrupts cholesterol biosynthesis by activating the mevalonate pathway and suppressing terminal enzymes.
- Alisol B downregulates the BIRC5-FOXM1-ITGA4 oncogenic axis and SCD5, impairing cancer cell survival.

## Abstract

Glioblastoma (GBM) is a highly aggressive and therapy-resistant brain tumor, necessitating innovative multi-target strategies. Natural compounds like the triterpenoid Alisol B from Alisma orientale hold promise due to their polypharmacological potential, yet their system-level mechanisms are unclear. Using an integrated multi-omics approach (transcriptomics, proteomics, lysine acetyl-proteomics) in resistant GBM cells and validating findings in vitro and in AB strain zebrafish (Danio rerio) xenografts, we found that Alisol B induces endoplasmic reticulum stress and G2/M arrest, initiated by extensive lysine acetylation reprogramming on histones and metabolic enzymes (e.g., FASN, FDFT1). This epigenetic rewiring leads to disrupted cholesterol biosynthesis, characterized by transcriptional activation of the mevalonate pathway alongside post-transcriptional suppression of terminal enzymes (DHCR7, CYP51A1), suggestive of toxic intermediate accumulation. Alisol B also downregulated the oncogenic axis (BIRC5-FOXM1-ITGA4) and SCD5. This study delineates Alisol B’s novel multi-mechanistic action through concurrent epigenetic rewiring, metabolic dysfunction induction, and survival network dismantling. Our work elucidates the molecular pharmacology of a natural compound and provides a framework for developing polypharmacological therapies against resistant cancers, exemplifying natural products as tools to reveal new therapeutic paradigms.