Evidence map›Paper›PMID 42204622›Full record

ArticleBiology direct2026

Dual inhibition of KDM4B and KDM5A disassembles the PAX3-FOXO1 transcriptional program in fusion-positive rhabdomyosarcoma.

Junhong Yuan, Qilei Han, Pengxuan Ren, Fang Bai, Xianglei Zhang, Kai Li

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Article in Biology direct, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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1 · What the graph read from it

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3 · Its place in the literature

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4 · The record

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5 · Who and what money

Authors and funding

6 authors.

Junhong YuanDepartment of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, 201210, China.
Qilei HanShanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
Pengxuan RenShanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
Fang BaiShanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
Xianglei ZhangShanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. zhangxl6@shanghaitech.edu.cn.
Kai LiDepartment of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, 201210, China. likai2727@163.com.

Funding

Cyrus Tang Foundation ZSBK0070Incubation Project of "Medicine+X" Interdisciplinary Innovation Team of Children's Hospital of Fudan University PT000384National Clinical Key Specialty Construction Project 10000015Z155080000004"Pioneer" and "Leading Goose" R&D Program of Zhejiang Province (J.W.) 2024C03181Shanghai Municipal Commission of Science and Technology 24JS2850100Top-notch Talents Project of Shanghai Municipal Oriental Elite Program BJW2025031
6 · The paper itself

Abstract

backgroundFusion-positive rhabdomyosarcoma (FP-RMS) is driven by the oncogenic transcription factor PAX3-FOXO1 and is associated with poor clinical outcome. The histone demethylase KDM4B has been implicated in sustaining PAX3-FOXO1-dependent transcriptional programs, but the epigenetic regulatory mechanisms supporting this network remain incompletely characterized.

methodsWe employed a deep learning-based drug discovery strategy and identified a novel small-molecule, Compound 01. Functional and mechanistic analyses were then performed to delineate cooperative interactions among KDM4B, KDM5A, and PAX3-FOXO1, and to evaluate the impact of pharmacological perturbation on the stability of this transcriptional network in FP-RMS models.

resultsIn this study, we identified Compound 01 with dual activity against KDM4B and KDM5A that triggers proteasome-dependent loss of both proteins. Mechanistically, we uncover a reciprocal stabilization loop in which KDM4B, KDM5A, and PAX3-FOXO1 reinforce each other to sustain the PAX3-FOXO1 transcriptional state. Pharmacological disruption of this axis by Compound 01 collapses the PAX3-FOXO1-driven oncogenic transcriptional program, suppresses key downstream targets, and markedly impairs FP-RMS cell proliferation and metastatic potential.

conclusionThese findings identify KDM5A as a critical epigenetic partner of the PAX3-FOXO1 network and establish dual KDM4B/KDM5A targeting as a strategy to destabilize PAX3-FOXO1 transcriptional circuitry in FP-RMS.

Indexed as

Jumonji Domain-Containing Histone DemethylasesOncogene Proteins, FusionRetinoblastoma-Binding Protein 2RhabdomyosarcomaAnimalsCell Line, TumorGene Expression Regulation, NeoplasticHumansPaired Box Transcription FactorsPAX3 Transcription FactorTranscription, GeneticJumonji Domain-Containing Histone DemethylasesKDM4B protein, humanKDM5A protein, humanOncogene Proteins, FusionPaired Box Transcription FactorsPAX3-FOXO1A fusion protein, humanPAX3 Transcription FactorRetinoblastoma-Binding Protein 2Deep learning-based screeningFusion-positive rhabdomyosarcomaHistone demethylasesPAX3-FOXO1Transcriptional circuitry

Identifiers

PMID42204622
PMCPMC13419031

What Socratic holds

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LicenceCC BY-NC-ND
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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.