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Cited by 0Ferroptosis and cancer prognosisProtein Degradation and InhibitorsHistone Deacetylase Inhibitors Research

An HDAC4-specific PROTAC degrader achieves radiation sensitization by enhancing ferroptosis in lung cancer

Open access
Cheng, Chun, Sun, Longhua, Yang, Jiaxue, Liu, Zhiliang, Zhang, Fan, Qiu, Lingyan, Yu, Meng, Wang, Ting +6 more·2026·Nature Communications
DOI 10.1038/s41467-026-73682-0PMC PMC13389272
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Abstract

Post-translational modifications (PTMs) play a critical role in cancer radioresistance, yet how they regulate ferroptosis to influence radiotherapy response remains poorly understood. Here, we show that HDAC4 promotes radiation resistance in lung cancer by inhibiting ferroptosis. Through a CRISPR screen in patient-derived organoids, we identify HDAC4 as a key mediator. Mechanistically, HDAC4 acts as an E3 SUMO ligase that SUMOylates MBD1, preventing its ubiquitination and degradation. Stabilized MBD1 represses TP53 and CYP1A1 transcription, thereby suppressing lipid reactive oxygen species formation and ferroptosis. To target HDAC4, we develop a proteolysis-targeting chimera (PROTAC), TP1, based on tasquinimod, which binds and degrades HDAC4 specifically, as confirmed by surface plasmon resonance and proteomics. TP1 exhibits stronger radiosensitizing effects than tasquinimod in lung cancer organoids and xenograft models. Our findings uncover HDAC4 as a suppressor of ferroptosis in radioresistance and present a PROTAC-based strategy to enhance radiotherapy efficacy. Posttranslational modification of proteins plays a role in radioresistance. Here the authors find that histone deacetylase 4 (HDAC4) mediates radiation resistance in lung cancer by promoting MBD1 SUMOylation, leading to inhibition of lipid peroxidation as well as ferroptosis.

AI snapshot

Written from the paper’s full text.

TL;DR

In lung cancer, HDAC4 promotes radioresistance by acting as an E3 SUMO ligase that stabilizes MBD1, represses TP53 and CYP1A1, and suppresses ferroptosis. A tasquinimod-based PROTAC, TP1, selectively degrades HDAC4 and radiosensitizes lung cancer organoids and xenografts more effectively than tasquinimod.

Key findings

  • A CRISPR screen of 903 posttranslational-modification-related proteins in LCO-1 and LCO-4 organoids identified HDAC4 among the top 20 downregulated genes common to both; HDAC4 protein was 2.14-fold higher in lung cancer tissues than in normal lung cells (4.29 ± 2.15 vs. 2.00 ± 1.24), and IR increased HDAC4 in 5 of 6 organoids.
  • HDAC4’s E3 SUMO ligase activity, rather than its deacetylase activity, drove radioresistance and ferroptosis suppression; HDAC4 SUMOylated MBD1 at K366, reducing MBD1 ubiquitination and stabilizing it, while stabilized MBD1 repressed TP53 and CYP1A1 and lowered lipid ROS.
  • TP1 bound HDAC4 with a KD of 88.24 nM (tasquinimod, 36.45 nM), induced CRBN-dependent HDAC4 ubiquitination/degradation, and had IC50 values of 1.27 μM in A549 and 0.86 μM in H460 cells; TP1 increased lipid ROS and outperformed tasquinimod in radiosensitizing LCO-4 organoids and xenografts (n = 6 per group, 10 mg/kg).

Methods

  • Patient-derived LUAD organoids were established from 7 surgically resected tumors (6/7 initiated), alongside normal bronchial organoids; a pooled CRISPR screen targeting 903 PTM-related proteins was performed in LCO-1 and LCO-4 with or without 9 Gy IR for 10 days and analyzed with MAGeCK/MAGeCKFlute.
  • Mechanistic validation used co-IP, proximity ligation assay, SUMOylation/ubiquitination assays, ChIP, CUT&Tag (n = 1), qRT-PCR, western blotting, C11-BODIPY flow cytometry for lipid ROS, transmission electron microscopy, SPR, SPPIER/BiFC, and DIA proteomics.
  • In vivo testing used cell-derived xenografts in 42 male athymic nude mice; TP1 or tasquinimod was given at 10 mg/kg every 3 days for 2 weeks with or without 6 Gy IR, with tumor weights and IHC assessed. Clinical material included 42 lung cancer specimens, 3 paired pre/post-radiotherapy samples, and a 120-sample tissue microarray; statistics used t tests, ANOVA, and χ2 tests.

Limitations

  • Stated: TP1 requires 10 μM treatment within 24 h for effective degradation and is derived from the polypharmacological tasquinimod scaffold, so further structure-activity relationship studies and orthogonal target engagement validation are needed.
  • Stated: the findings are primarily from cell lines, patient-derived organoids, and immunodeficient xenograft models, which do not fully recapitulate the tumor microenvironment and immune responses influencing radiotherapy; immunocompetent models are warranted.
  • Evident: several key analyses were n = 1 (CRISPR screen, tandem affinity purification/mass spectrometry, CUT&Tag), limiting statistical robustness; xenografts used only male athymic nude mice, so sex-specific and immune contributions were not assessed.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41467-026-73682-0

Cites

78 of 80 references verified0 citation errors · 2 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

33 of 38 cited sources checked · 22 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Combination of ferroptosis inducers significantly increases the killing effect of IR on tumor cells.

    “the combination of ferroptosis inducers significantly increases the killing effect of IR on tumor cells12.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [12] Lei, G. et al. The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression. Cell Res. 30, 146–162 (2020). source
  • Premisecitation

    p53 directly inhibits the transcription of SLC7A11, a key transporter of cysteine that imports extracellular cystine into cells.

    “p53 directly inhibits the transcription of SLC7A11, a key transporter of cysteine that imports extracellular cystine into cells37.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [37] Jiang, L. et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature 520, 57–62 (2015). source
  • Premisecitation

    CYP1A1 increases ROS levels to promote lipid ROS formation.

    “CYP1A1 increases ROS levels to promote lipid ROS formation38.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [38] Panda, S. K. et al. Repression of the aryl-hydrocarbon receptor prevents oxidative stress and ferroptosis of intestinal intraepithelial lymphocytes. Immunity 56, 797–812 e794 (2023). source
  • Premisecitation

    Modification of the E3 ligands prevents the recruitment of their respective E3 ligases by the PROTAC, allowing assessment of PROTAC activity in the absence of the E3 ligase.

    “The modification of the E3 ligands prevents the recruitment of their respective E3 ligases by the PROTAC, thereby allowing the assessment of the activity of the PROTAC in the absence of the E3 ligase45,46.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [45] Lebraud, H., Wright, D. J., Johnson, C. N. & Heightman, T. D. Protein degradation by in-cell self-assembly of proteolysis targeting Chimeras. ACS Cent. Sci. 2, 927–934 (2016). source

      The Introduction describes methylated Tz-thalidomide as a control that disrupts binding to CRBN, and the Results (BRD4 Degradation by CLIPTAC) report no BRD4 degradation with that control. This supports testing activity without effective CRBN recruitment, but the paper does not establish the claim for E3 ligands generally or test activity in cells physically lacking the E3 ligase. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [46] Aublette, M. C., Harrison, T. A., Thorpe, E. J. & Gadd, M. S. Selective Wee1 degradation by PROTAC degraders recruiting VHL and CRBN E3 ubiquitin ligases. Bioorg. Med. Chem. Lett. 64, 128636 (2022). source
  • Premisecitation

    TP1 contains an IMiD moiety that interacts with the E3 ligase receptor CRBN.

    “Since TP1 contains an IMiD moiety that interacts with the E3 ligase receptor CRBN43,44”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [43] Petzold, G., Fischer, E. S. & Thoma, N. H. Structural basis of lenalidomide-induced CK1alpha degradation by the CRL4(CRBN) ubiquitin ligase. Nature 532, 127–130 (2016). source
    • cites [44] Lopez-Girona, A. et al. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia 26, 2326–2335 (2012). source

      The Discussion reports that immunomodulatory compounds bind CRBN within an E3 ligase complex, specifically through their glutarimide moiety. The paper does not identify TP1 or establish that TP1 contains such a moiety, so it supports the binding rationale but not the TP1-specific claim. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • May combine two claims. 56
  • Classified as probably not a substantial claim. 38

  • May combine two claims.

    Premisecitation

    GPX4 is a key repressor of ferroptosis, and its activity depends on glutathione production from SLC7A11.

    “The selenium-containing enzyme GPX4 is currently recognized as a key repressor of ferroptosis, and its activity depends on the production of glutathione from the activation of the cystine-glutamate antiporter SLC7A1111.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [11] Chen, X., Li, J., Kang, R., Klionsky, D. J. & Tang, D. Ferroptosis: machinery and regulation. Autophagy 17, 2054–2081 (2021). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    HDAC4 has minimal deacetylase enzymatic activity towards acetyl-lysine.

    “Despite having minimal deacetylase enzymatic activity towards acetyl-lysine16”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [16] Cuttini, E., Goi, C., Pellarin, E., Vida, R. & Brancolini, C. HDAC4 in cancer: A multitasking platform to drive not only epigenetic modifications. Front.Mol. Biosci. 10, 1116660 (2023). source

  • May combine two claims.

    Premisecitation

    Ionizing radiation can promote ferroptosis by inducing ROS production but also induce upregulation of SLC7A11 and GPX4, resulting in negative feedback and radiation resistance.

    “Ionizing radiation (IR) can not only promote ferroptosis by inducing reactive oxygen species (ROS) production but also induce the upregulation of SLC7A11 and GPX4 expression, resulting in negative feedback, ultimately leading to radiation resistance”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [12] Lei, G. et al. The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression. Cell Res. 30, 146–162 (2020). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    HDAC4 can function as a platform to coordinate the activity of class I HDACs.

    “HDAC4 can function as a platform to coordinate the activity of class I HDACs16.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [16] Cuttini, E., Goi, C., Pellarin, E., Vida, R. & Brancolini, C. HDAC4 in cancer: A multitasking platform to drive not only epigenetic modifications. Front.Mol. Biosci. 10, 1116660 (2023). source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Compared with traditional occupancy-based inhibitors, PROTACs offer advantages in dosing precision, side effect management, drug resistance prevention, and modulation of undruggable targets.

    “Compared with traditional occupancy-based inhibitors, PROTACs offer several advantages with respect to dosing precision, side effect management, drug resistance prevention, and the modulation of ‘undruggable’ targets21,22.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [21] Li, K. & Crews, C. M. PROTACs: past, present and future. Chem. Soc. Rev. 51, 5214–5236 (2022). source

      The Abstract and Conclusions describe advantages over occupancy-driven inhibitors, including reduced dosing, potential reductions in toxicity, efficacy despite resistance mechanisms, and expanded target space. They do not establish more precise dosing or prevention of drug resistance: reduced dosing is not the same as dosing precision, and overcoming resistance is not the same as preventing it. The cited passages have section labels but no page numbers. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [22] Schapira, M., Calabrese, M. F., Bullock, A. N. & Crews, C. M. Targeted protein degradation: expanding the toolbox. Nat. Rev. Drug Discov. 18, 949–963 (2019). source

      The Abstract (p. 2) describes potential advantages over occupancy-based inhibitors in dosing, side effects, drug resistance, and modulating ‘undruggable’ targets. The claim presents those potential advantages as established and specifies dosing precision and resistance prevention, which the source does not establish; Progress and lessons learned (p. 6) instead notes dosing challenges and possible acquired resistance to PROTACs. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Multiple PROTACs have been developed to overcome drug resistance in NSCLC.

    “Multiple PROTACs have been developed to overcome drug resistance in NSCLC23”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [23] Li, J. W., Zheng, G., Kaye, F. J. & Wu, L. PROTAC therapy as a new targeted therapy for lung cancer. Mol. Ther.: J. Am. Soc. Gene Ther. 31, 647–656 (2023). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Tasquinimod, a specific inhibitor of HDAC4, effectively inhibits growth and metastasis of tumor cells in vitro and in vivo.

    “tasquinimod, a specific inhibitor of HDAC4, has been shown to effectively inhibit the growth and metastasis of tumor cells both in vitro and in vivo15.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [15] Cheng, C. et al. HDAC4 promotes nasopharyngeal carcinoma progression and serves as a therapeutic target. Cell Death Dis. 12, 137 (2021). source

      The Results report that tasquinimod reduced NPC-cell proliferation, migration, and invasion in vitro and tumor growth in vivo (Figs. 5–7). They do not report an in vivo metastasis result. The paper also describes tasquinimod as HDAC4-selective but notes a predicted interaction with HDAC7, so calling it a specific HDAC4 inhibitor is stronger than the evidence shown. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    HDAC4 is a member of class IIa HDACs, which play a role in tumorigenesis of multiple cancers.

    “Histone deacetylase 4 (HDAC4) is a member of the class IIa HDACs, which play a role in the tumorigenesis of multiple cancers13–15.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [13] Zang, W. J. et al. HDAC4 promotes the growth and metastasis of gastric cancer via autophagic degradation of MEKK3. Br. J. Cancer 127, 237–248 (2022). source
    • cites [14] Wang, Z., Qin, G. & Zhao, T. C. HDAC4: mechanism of regulation and biological functions. Epigenomics 6, 139–150 (2014). source
    • cites [15] Cheng, C. et al. HDAC4 promotes nasopharyngeal carcinoma progression and serves as a therapeutic target. Cell Death Dis. 12, 137 (2021). source

  • Classified as probably not a substantial claim.

    Premisecitation

    Ferroptosis is an iron-dependent and lipid peroxidation-driven cell death cascade.

    “ferroptosis, an iron-dependent and lipid peroxidation-driven cell death cascade, has recently been identified7,8.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [7] Lei, G., Zhuang, L. & Gan, B. Targeting ferroptosis as a vulnerability in cancer. Nat. Rev. Cancer 22, 381–396 (2022). source
    • cites [8] Zhao, L. et al. Ferroptosis in cancer and cancer immunotherapy. Cancer Commun. 42, 88–116 (2022). source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    HDAC4 belongs to the SUMO E3 ligase family and can directly SUMOylate IκBα, AR, LXRα, and MEF2.

    “Additionally, HDAC4 belongs to the SUMO E3 ligase family and can directly SUMOylate IκBα, AR, LXRα, and MEF217–20.”
    Quote in the paperNot a substantial claim4 of 4 sources checked
    • cites [17] Yang, Q. et al. Histone deacetylase 4 inhibits NF-kappaB activation by facilitating IkappaBalpha sumoylation. J. Mol. Cell Biol. 12, 933–945 (2020). source

      The Results section (‘HDAC4 catalyzes the sumoylation of IκBα’; page not available) reports that HDAC4 directly mediates IκBα SUMOylation as a SUMO E3 ligase. The Introduction and Results also report HDAC4-mediated SUMOylation of LXRα and MEF2, but do not establish that it is direct; no passage found supports AR SUMOylation. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [18] Zhao, X., Sternsdorf, T., Bolger, T. A., Evans, R. M. & Yao, T. P. Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications. Mol. Cell. Biol. 25, 8456–8464 (2005). source
    • cites [19] Lee, J. H. et al. Differential SUMOylation of LXRalpha and LXRbeta mediates transrepression of STAT1 inflammatory signaling in IFN-gamma-stimulated brain astrocytes. Mol. Cell 35, 806–817 (2009). source

      The Results report that HDAC4 acts as a SUMO E3 ligase and that LXRα was SUMOylated by HDAC4 in brain astrocytes, with in vitro assays providing further confirmation. Our copy does not report HDAC4 directly SUMOylating IκBα, AR, or MEF2; MEF2 appears in cited references, not as a substrate tested here. Page numbers are unavailable in the indexed copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [20] Yang, Y. et al. Inhibition of androgen receptor activity by histone deacetylase 4 through receptor SUMOylation. Oncogene 30, 2207–2218 (2011). source

      The Results section reports that HDAC4 increases AR SUMOylation. The Discussion describes HDAC4 as a *possible* SUMO E3 ligase, notes reports concerning MEF2 and LXR, and says AR SUMOylation might instead be enhanced through other E3 enzymes. It does not establish direct SUMOylation of all four named proteins, and the searched passages do not address IκBα. Page numbers were not supplied. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Flexible linkers, dominated by alkyl chains and PEG, are widely used.

    “Flexible linkers, dominated by alkyl chains and PEG, are widely used42.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [42] Dong, Y. et al. Characteristic roadmap of linker governs the rational design of PROTACs. Acta Pharm. Sin. B 14, 4266–4295 (2024). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The composition and length of linkers can affect the efficiency of degraders.

    “The composition and length of linkers can affect the efficiency of degraders40,41.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [40] Bekes, M., Langley, D. R. & Crews, C. M. PROTAC targeted protein degraders: the past is prologue. Nat. Rev. Drug Discov. 21, 181–200 (2022). source
    • cites [41] Troup, R. I., Fallan, C. & Baud, M. G. J. Current strategies for the design of PROTAC linkers: a critical review. Explor. Target. Anti-tumor Ther. 1, 273–312 (2020). source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Tasquinimod is a small-molecule compound that binds to HDAC4 and is believed to inhibit the transcription of downstream target genes by inhibiting the formation of HDAC3/N-CoR complexes.

    “Tasquinimod is a small-molecule compound that binds to HDAC4 and is believed to inhibit the transcription of downstream target genes by inhibiting the formation of HDAC3/N-CoR complexes39.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [39] Isaacs, J. T. et al. Tasquinimod is an allosteric modulator of HDAC4 survival signaling within the compromised cancer microenvironment. Cancer Res. 73, 1386–1399 (2013). source

      The Results sections on allosteric binding and complex formation report that tasquinimod binds HDAC4 and prevents its association with N-CoR/HDAC3. The paper links this mechanism to reduced HIF-1-dependent transcription, but does not support a general inhibition of downstream gene transcription: it also says HDAC3 represses transcription associated with most HDAC4 client transcription factors. Page numbers are unavailable in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S2 (checkable).

    Premisecitation

    Proteolysis-targeting chimeras (PROTACs) offer a powerful strategy for antitumor drug discovery.

    “Proteolysis-targeting chimeras (PROTACs) offer a powerful strategy for antitumor drug discovery40.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [40] Bekes, M., Langley, D. R. & Crews, C. M. PROTAC targeted protein degraders: the past is prologue. Nat. Rev. Drug Discov. 21, 181–200 (2022). source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Cancer organoids maintain the physiological structure and function of their source tissue and are widely used in research on tumor pathogenesis, drug development, treatment resistance, and other fields.

    “Cancer organoids, which maintain the physiological structure and function of their source tissue, are widely used in research on tumor pathogenesis, drug development, treatment resistance, and other fields48,49.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [48] Gronholm, M. et al. Patient-derived organoids for precision cancer immunotherapy. Cancer Res. 81, 3149–3155 (2021). source

      The Patient-derived organoids section says tumor organoids resemble their source tissue, retain key genetic and phenotypic features, and are used to model disease progression and test drugs. The Complex organoids and immunotherapy section also describes studying resistance mechanisms, but specifically with immune-enhanced organoids. The claim overstates preservation of tissue function generally: the Complex organoids section says tumor organoids do not fully recapitulate the tumor microenvironment. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [49] Yang, R. & Yu, Y. Patient-derived organoids in translational oncology and drug screening. Cancer Lett. 562, 216180 (2023). source

  • May combine two claims.

    Premisecitation

    IR promotes lipid peroxidation and ferroptosis by inducing ROS production and upregulating ACSL4 expression; however, it also upregulates the ferroptosis-inhibiting proteins SLC7A11 and GPX4 to counteract ferroptosis.

    “IR promotes lipid peroxidation and ferroptosis by inducing ROS production and upregulating ACSL4 expression; however, it also upregulates the expression of the ferroptosis-inhibiting proteins SLC7A11 and GPX4 to counteract ferroptosis12.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [12] Lei, G. et al. The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression. Cell Res. 30, 146–162 (2020). source

  • May combine two claims.

    Premisecitation

    Inhibition of SLC7A11 and GPX4 can promote ferroptosis and sensitize radiation-resistant cells to IR.

    “The inhibition of SLC7A11 and GPX4 can promote ferroptosis and sensitize radiation-resistant cells to IR12.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [12] Lei, G. et al. The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression. Cell Res. 30, 146–162 (2020). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The contribution of HDAC4 to ferroptosis in different diseases seems to be context-dependent.

    “which indicates that the contribution of HDAC4 to ferroptosis in different diseases seems to be context-dependent.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [52] Martin, S. D. et al. Class IIa HDACs inhibit cell death pathways and protect muscle integrity in response to lipotoxicity. Cell Death Dis. 14, 787 (2023). source

      The Results section reports that HDAC4 and HDAC5 suppress ferroptosis-related processes in myoblasts and skeletal muscle under lipotoxic conditions. The paper does not compare HDAC4’s effects across different diseases, and its experiments assess HDAC4 together with HDAC5, so it does not establish the claimed cross-disease context dependence. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    NBOs expressed TP63 and KRT5.

    “The results demonstrated that the NBOs expressed the markers TP63 and KRT5, which are markers of normal lung basal cells”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    At least 30% of the organoids were Ki67 positive.

    “at least 30% of the organoids were Ki67 positive”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    LCOs derived from adenocarcinoma tissue produced acinar or large glandular patterns and retained expression of TTF-1 and CK7.

    “Like their parental cancer tissue, LCOs derived from adenocarcinoma tissue produced acinar or large glandular patterns and retained the expression of the lung adenocarcinoma markers thyroid transcription factor 1 (TTF-1) and cytokeratin 7 (CK7).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    TP1 is a PROTAC based on tasquinimod that binds and degrades HDAC4 specifically.

    “To target HDAC4, we develop a proteolysis-targeting chimera (PROTAC), TP1, based on tasquinimod, which binds and degrades HDAC4 specifically, as confirmed by surface plasmon resonance and proteomics.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The polyubiquitination of the K366R mutant did not differ between the control group and the HDAC4-overexpressing group or between the control and HDAC4-knockdown groups.

    “the polyubiquitination of the K366R mutant did not differ between the control group and the HDAC4-overexpressing group or between the control and HDAC4-knockdown groups (Fig. 4j, k).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Tasquinimod does not inhibit the interaction between HDAC4 and MBD1 but effectively disrupts the formation of HDAC4/HDAC3/N-CoR complexes.

    “tasquinimod, which does not inhibit the interaction between HDAC4 and MBD1 (Supplementary Fig. 7a) but effectively disrupts the formation of HDAC4/HDAC3/N-CoR complexes (Supplementary Fig. 7b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    10 μM TP1 achieved optimal degradation within 24 h, but low-dose TP1 achieved optimal degradation within 48 h.

    “Time-course studies revealed that 10 μM TP1 achieved optimal degradation within 24 h (Fig. 6b), but low-dose TP1 achieved optimal degradation within 48 h (Supplementary Fig. 7i).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    MBD1-WT effectively alleviated the lipid-ROS induced by HDAC4 knockdown, whereas K366R did not, after IR.

    “MBD1-WT could effectively alleviate the lipid-ROS induced by HDAC4 knockdown, whereas K366R did not (Fig. 5m, n) after IR.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Overexpression or knockdown of HDAC4 increased or inhibited the MBD1 protein level but not the MBD1 mRNA level.

    “the overexpression or knockdown of HDAC4 increased or inhibited the MBD1 protein level but not the MBD1 mRNA level”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    WT HDAC4 increased the SUMO3 modification level of MBD1, whereas a SUMO ligase-inactive variant did not.

    “WT HDAC4 increased the SUMO3 modification level of MBD1, whereas the inactive variant did not”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    MBD1-WT reversed the cell death induced by HDAC4 knockdown after IR, whereas the K366R mutant did not.

    “MBD1-WT reversed the cell death induced by HDAC4 knockdown after IR, whereas the K366R mutant did not (Fig. 5o, p).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    HDAC4 knockdown caused shrunken mitochondria, increased membrane density, and ruptured outer mitochondrial membrane.

    “we observed shrunken mitochondria, increased membrane density, and ruptured outer mitochondrial membrane following HDAC4 knockdown, which are characteristic of ferroptosis”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    HDAC4 and MBD1 can both be found in the nucleus.

    “IF analysis revealed that they can both be found in the nucleus as expected”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    TP1 effectively reduced the HDAC4 protein concentration but TP2 did not significantly reduce the HDAC4 protein concentration in A549 and H460 cells with high CRBN expression.

    “The results showed that TP1 effectively reduced the HDAC4 protein concentration but that TP2 did not significantly reduce the HDAC4 protein concentration (Supplementary Fig. 7g, h).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The interaction between HDAC4 and MBD1 is maintained after IR, with an increased amount of the complex.

    “the interaction between HDAC4 and MBD1 was maintained after IR, with an increased amount of the complex observed”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Ectopic WT and mutant (H803A, D840N) HDAC4 proteins decreased lipid ROS accumulation and cell death compared with control, but SUMOylation inactivation (C292S) did not.

    “Although the ectopic WT and mutant (H803A, D840N) HDAC4 proteins decreased lipid ROS accumulation and cell death compared with those in the control group, we did not observe any changes in lipid ROS accumulation or cell death caused by IR during SUMOylation-induced enzymatic inactivation”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    HDAC4 knockdown resulted in a shorter half-life for WT MBD1 but not for the K366R mutant.

    “HDAC4 knockdown by shRNA resulted in a shorter half-life for WT MBD1 but not for the K366R mutant”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    HDAC4 overexpression significantly increased the SUMOylation of wild-type MBD1, but not the K366R mutant.

    “HDAC4 overexpression significantly increased the SUMOylation of wild-type MBD1, but not the K366R mutant”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    IR significantly increases the HDAC4-MBD1 interaction, predominantly within the nucleus.

    “the IF results demonstrated a significant increase in the HDAC4–MBD1 interaction postirradiation, which was predominantly localized within the nucleus”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CRISPR-Cas9 produced A549 cells with stable disruption of the CRBN gene; western blot revealed loss of CRBN expression in CRBN-edited cells and retained expression in control-edited cells.

    “we used CRISPR–Cas9 gene editing to produce A549 cells with stable disruption of the CRBN gene. Western blotting of lysates prepared from control and CRBN-edited A549 cells revealed the loss of CRBN expression in CRBN-edited cells, with retained expression in control-edited cells (Supplementary Fig. 7l).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TP1 suppressed HDAC4 and MBD1 expression in control A549 cells but not in CRBN-edited cells.

    “TP1 suppressed HDAC4 and MBD1 expression; the same effect was not observed in CRBN-edited cells (Supplementary Fig. 7l).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In TP1-treated cells, p53 expression was upregulated, SLC7A11 expression was downregulated, and CYP1A1 expression was increased, consistent with HDAC4 knockdown.

    “In TP1-treated cells, the expression of the ferroptosis regulator p53 was upregulated, and the expression of the ferroptosis mediator SLC7A11 was downregulated (Fig. 7a–d); additionally, CYP1A1 expression was increased, a finding that was consistent with the effects of the shRNA-mediated knockdown of HDAC4 (Fig. 5d, f).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TP1 inhibited the growth of A549 and H460 cells, with IC50 values of 1.27 μM and 0.86 μM, respectively.

    “In A549 and H460 cells, TP1 inhibited the growth of A549 and H460 cells, with IC50 values of 1.27 μM and 0.86 μM (Supplementary Fig. 8a), respectively.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The synthesized small-molecule PROTAC has high affinity for HDAC4, with a KD of 88.24 nM.

    “Through SPR experiments, we found that our small-molecule PROTAC had a high affinity for HDAC4, reaching 88.24 nM.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    MBD1 and SLC7A11 decreased after treatment with TP1 but not with tasquinimod.

    “Moreover, MBD1 and SLC7A11 also decreased after treatment with TP1 but not with tasquinimod (Supplementary Fig. 8l).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TP1 treatment had a similar effect as HDAC4 knockdown, both of which enhanced radiotherapy sensitivity more than tasquinimod did.

    “TP1 treatment had a similar effect as that of HDAC4 knockdown, both of which enhanced radiotherapy sensitivity more than tasquinimod did (Fig. 7k, l).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TP1, but not tasquinimod, induced the generation of yellow fluorescent droplets indicating ternary complex formation.

    “TP1, but not tasquinimod, induced the generation of yellow fluorescent droplets (Fig. 6h).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In LCO-1, -2, -3, -4 and -6 organoids, the levels of HDAC4, MBD1, and SLC7A11 decreased after TP1 treatment, whereas p53 and CYP1A1 protein levels increased.

    “In LCO-1, -2, -3, -4 and -6 organoids, the levels of mediators of HDAC4 signaling, including HDAC4, MBD1, and SLC7A11, decreased after TP1 treatment, whereas p53 and CYP1A1 protein levels increased (Fig. 8c and Supplementary Fig. 9a–d).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    HDAC4-VN173 and CRBN-VC155 were localized in the cytoplasm.

    “HDAC4-VN173 and CRBN-VC155 were localized in the cytoplasm (Fig. 6i).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Knocking down HDAC4 enhanced radiotherapy sensitivity, whereas overexpressing HDAC4 enhanced radiotherapy resistance.

    “functional experiments revealed that knocking down HDAC4 enhanced radiotherapy sensitivity, whereas overexpressing HDAC4 enhanced radiotherapy resistance”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In H460 and A549 cells, TP1 more strongly inhibited cell growth and colony formation than tasquinimod and suppressed the cell cycle.

    “in H460 and A549 cells, TP1 more strongly inhibited cell growth and colony formation than did tasquinimod and suppressed the cell cycle (Supplementary Fig. 8b–i).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Treatment with 10 μM negTP1 for 24 h left the HDAC4 protein level unchanged, indicating that interfering with binding to CRBN blocks HDAC4 degradation.

    “We then treated H460 and A549 cells with 10 μM negTP1 for 24 h. The protein level of HDAC4 remained unchanged (Supplementary Fig. 7k), indicating that interfering with the binding to CRBN blocks HDAC4 degradation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TP1 and tasquinimod had very strong affinities for the HDAC4 protein, with KD values of 88.24 nM and 36.45 nM, respectively.

    “compounds TP1 and tasquinimod had very strong affinities for the HDAC4 protein, and the KD values were 88.24 nM and 36.45 nM, respectively.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    LCO-1 and LCO-4 organoids with higher HDAC4 expression had a lower IC50 for TP1, whereas LCO-2 and LCO-5 organoids with lower HDAC4 expression had a higher IC50.

    “LCO-1 and LCO-4 organoids with higher HDAC4 expression had a lower IC50, whereas LCO-2 and LCO-5 organoids with lower HDAC4 expression had a higher IC50 (Fig. 8a).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Radiation produces reactive oxygen species, which can lead to oxidation of biomolecules such as lipids.

    “In addition to DNA damage, radiation also produces reactive oxygen species, which can lead to the oxidation of biomolecules, such as lipids6.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Wolters, H., van Tilburg, C. A. & Konings, A. W. Radiation-induced lipid peroxidation: influence of oxygen concentration and membrane lipid composition. Int. J. Radiat. Biol. Relat. Stud. Phys. Chem. Med. 51, 619–628 (1987). source

  • May combine two claims.

    Interpretationown data

    The panel of LUAD organoids closely recapitulated the histology and genomics of patient tumors and could be used to discover or validate potential radioresistance targets.

    “Overall, our data indicate that our panel of LUAD organoids closely recapitulated the histology and genomics of patient tumors and could be used to discover or validate potential radioresistance targets.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Stabilized MBD1 represses TP53 and CYP1A1 transcription, thereby suppressing lipid ROS formation and ferroptosis.

    “Stabilized MBD1 represses TP53 and CYP1A1 transcription, thereby suppressing lipid reactive oxygen species formation and ferroptosis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    HDAC4 promotes MBD1 protein stability via SUMOylation at K366, which reduces the polyubiquitination of MBD1 and prevents its subsequent degradation.

    “our results strongly indicate that HDAC4 promotes MBD1 protein stability via SUMOylation at K366, which reduces the polyubiquitination of MBD1 and prevents its subsequent degradation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The deacetylase activity of HDAC4 contributes only partially to radioresistance in lung cancer cells, which is predominantly driven by its E3 SUMO ligase activity.

    “Taken together, these results indicate that the deacetylase activity of HDAC4 contributes only partially to radioresistance in lung cancer cells, which is predominantly driven by its E3 SUMO ligase activity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    HDAC4 facilitates the SUMO3 modification of MBD1, and IR can strengthen this effect.

    “These findings unequivocally establish that HDAC4 facilitates the SUMO3 modification of MBD1 and that IR can strengthen this effect.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    TP1 can serve as a radiosensitizer and promote ferroptosis in lung cancer.

    “These findings demonstrate that TP1 can serve as a radiosensitizer and promote ferroptosis in lung cancer.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    TP1 functions by binding to HDAC4, leading to the CRBN-dependent proteasomal degradation of HDAC4.

    “These data indicate that TP1 functions by binding to HDAC4, which leads to the CRBN-dependent proteasomal degradation of HDAC4.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    A small-molecule PROTAC compound based on tasquinimod effectively degrades HDAC4 and promotes lung cancer ferroptosis as well as sensitization to radiation therapy.

    “we developed a small-molecule PROTAC compound based on tasquinimod that effectively degrades HDAC4 and promotes lung cancer ferroptosis as well as sensitization to radiation therapy (Fig. 8h).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    IR-induced HDAC4 upregulation leads to increased SLC7A11 expression, which inhibits ferroptosis and sensitization to radiation; this partially explains the increase in SLC7A11 expression following IR treatment.

    “Our research demonstrated that IR-induced HDAC4 upregulation leads to the increased expression of SLC7A11, which inhibits ferroptosis and sensitization to radiation; this finding partially explains why there is an increase in SLC7A11 expression following IR treatment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    IR upregulates HDAC4 expression, which impedes lung cancer ferroptosis via its E3 SUMO activity and consequently enhances resistance to radiation therapy.

    “In this study, we employed lung cancer organoids in conjunction with CRISPR screening to reveal that IR upregulates HDAC4 expression, which impedes lung cancer ferroptosis via its E3 SUMO activity and consequently enhances resistance to radiation therapy.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The involvement of PTMs in mediating radioresistance associated with ferroptosis remains elusive.
    • Rests on an assumption: The relationship between MBD1 and ferroptosis is ambiguous.

  • May combine two claims.

    Interpretationown data

    LCOs could be used for predicting TP1 responses in vitro, as well as for proof-of-concept studies of targeted drugs based on HDAC4 expression.

    “These data demonstrated that our LCOs could be used for predicting TP1 responses in vitro, as well as for proof-of-concept studies of targeted drugs based on HDAC4 expression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    TasQ cannot effectively block HDAC4 E3 SUMO ligase activity, resulting in the inability to block the inhibitory effect of HDAC4 on ferroptosis.

    “Our experiments revealed that TasQ cannot effectively block HDAC4 E3 SUMO ligase activity, resulting in the inability to block the inhibitory effect of HDAC4 on ferroptosis.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: TasQ specifically binds to the Zn2+ domain of HDAC4 and inhibits its interaction with HDAC3 to block downstream target genes regulated by HDAC4.

  • May combine two claims.

    Interpretationown data

    HDAC4 facilitates the SUMOylation and stabilization of MBD1 while suppressing the expression of CYP1A1 and p53 to attenuate lipid ROS formation and promote lipid ROS degradation, respectively.

    “Mechanistically, our findings demonstrate that HDAC4 facilitates the SUMOylation and stabilization of MBD1 while suppressing the expression of CYP1A1 and p53 to attenuate lipid ROS formation and promote lipid ROS degradation, respectively.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The relationship between MBD1 and ferroptosis is ambiguous.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All studies were performed in accordance with the TRI-Council Policy Statement: Ethical Conduct for Research Involving Humans.

    “All studies were performed in accordance with the TRI-Council Policy Statement: Ethical Conduct for Research Involving Humans.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The use of human lung cancer tissues was approved by the Ethics Committee of the Third Affiliated Hospital of Nanchang University (KY2022042) and the Medical Ethics Committee of Jiangxi Cancer Hospital (2024ky210).

    “The use of human lung cancer tissues was reviewed and approved by the Ethics Committee of the Third Affiliated Hospital of Nanchang University (approval number: KY2022042) and the Medical Ethics Committee of Jiangxi Cancer Hospital (approval number: 2024ky210).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The study developed an inducer of ferroptosis that, in combination with radiation therapy, represents a potential therapeutic strategy.

    “In summary, our study provides evidence that HDAC4 promotes radiation resistance by stabilizing MBD1 to suppress ferroptosis in lung cancer and has led to the development of an inducer of ferroptosis, which, in combination with radiation therapy, represents a potential therapeutic strategy.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Preclinical findings from cell lines, organoids, and immunodeficient xenograft models can be used in clinical research.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The expression levels of HDAC4, MBD1, p53, SLC7A11, and CYP1A1 were scored using the semiquantitative immunoreactive score (IRS) scale described by Remmele and Stegner.

    “The expression levels of HDAC4, MBD1, p53, SLC7A11, and CYP1A1 were scored using the semiquantitative immunoreactive score (IRS) scale described by Remmele and Stegner71.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Remmele and Stegner71

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Each CRISPR library was sequenced to achieve over 500× average coverage.

    “Each library was sequenced to achieve over 500× average coverage, and the data were analyzed by MAGeCK72 and MAGeCKFlute73.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    Small-molecule compounds can be used in clinical research.

    “These findings suggest that small-molecule compounds can be used in clinical research.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Preclinical findings from cell lines, organoids, and immunodeficient xenograft models can be used in clinical research.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All in vitro experiments were performed at least three times independently.

    “All in vitro experiments were performed at least three times independently, and the mean values of three experiments are shown.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The collection of surgically resected primary tumors from patients with early-stage NSCLC and the development of organoids was approved by the Jiangxi Cancer Hospital Ethics Board.

    “The collection of surgically resected primary tumors from patients with early-stage NSCLC and the development of organoids was approved by the Jiangxi Cancer Hospital Ethics Board.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The use of WES data from patient-derived tumor tissues and matched organoids was approved by the Human Genetic Resources Administration of the Ministry of Science and Technology of China (approval number 2025BAT00973).

    “The use of WES data from patient-derived tumor tissues and matched organoids (LCOs) in this study has been approved by the Human Genetic Resources Administration of the Ministry of Science and Technology (MOST) of China (approval number: 2025BAT00973).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The cell lines used were authenticated via short tandem repeat profiling.

    “A549 (CCL-185), H460 (HTB-177), H522 (CRL-5810), H1155 (CRL-5818), H292 (CRL-1848), HCC827 (CRL-2868), and 293 T (CRL-3216) were obtained from American Type Culture Collection (ATCC; Manassas, VA, USA) and were authenticated via short tandem repeat profiling, tested for mycoplasma contamination, and cultured for less than two months.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The clinical diagnosis of NSCLC subtypes was validated via pathologic review.

    “The clinical diagnosis of NSCLC subtypes was validated via pathologic review.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The cell lines used were tested for mycoplasma contamination.

    “A549 (CCL-185), H460 (HTB-177), H522 (CRL-5810), H1155 (CRL-5818), H292 (CRL-1848), HCC827 (CRL-2868), and 293 T (CRL-3216) were obtained from American Type Culture Collection (ATCC; Manassas, VA, USA) and were authenticated via short tandem repeat profiling, tested for mycoplasma contamination, and cultured for less than two months.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Written informed consent was obtained from all patients.

    “Written informed consent was obtained from all patients.”
    • Also stated in: § Tumor tissue processing and organoid establishment · plain
      “Informed written consent was obtained from all patients.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The cell lines used were cultured for less than two months.

    “A549 (CCL-185), H460 (HTB-177), H522 (CRL-5810), H1155 (CRL-5818), H292 (CRL-1848), HCC827 (CRL-2868), and 293 T (CRL-3216) were obtained from American Type Culture Collection (ATCC; Manassas, VA, USA) and were authenticated via short tandem repeat profiling, tested for mycoplasma contamination, and cultured for less than two months.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Organoids were authenticated by whole-exome sequencing analysis and matched to patient tissue.

    “Organoids were authenticated by whole-exome sequencing (WES) analysis and matched to patient tissue.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All animal studies were performed in accordance with protocols approved by the Experimental Animal Science Center of Nanchang University (NCULAE-20230712001).

    “All the animal studies were performed in accordance with protocols approved by the Experimental Animal Science Center of Nanchang University (approval number: NCULAE-20230712001).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Organoid cultures were tested routinely for Mycoplasma.

    “Organoid cultures were tested routinely for Mycoplasma.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Mice were randomly assigned to experimental groups.

    “Suspensions were injected subcutaneously into the flanks of randomly assigned nude mice, which were monitored over 3 weeks.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All representative blots are derived from at least three independent experiments with similar results.

    “All representative blots are derived from at least three independent experiments with similar results.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    IHC staining was evaluated by two independent pathologists specializing in lung cancer.

    “IHC staining was evaluated by two independent pathologists specializing in lung cancer.”
    Quote in the paperNot a substantial claim
86 of 86

  • The paper relies on this without support.

    No investigation has been conducted to elucidate the relationship between the E3 SUMO activity of HDAC4 and radioresistance in lung cancer or other tumors.

    “However, no investigation has been conducted to elucidate the relationship between the E3 SUMO activity of HDAC4 and radioresistance in lung cancer or other tumors.”

  • The paper relies on this without support.

    The involvement of PTMs in mediating radioresistance associated with ferroptosis remains elusive.

    “Nevertheless, the involvement of PTMs in mediating radioresistance associated with ferroptosis remains elusive.”

  • The paper relies on this without support.

    The role of SUMO in regulating radiotherapy sensitivity through ferroptosis remains unclear.

    “However, the role of SUMO in regulating radiotherapy sensitivity through ferroptosis remains unclear.”

  • The paper relies on this without support.

    The relationship between MBD1 and ferroptosis is ambiguous.

    “acknowledging the ambiguous relationship between MBD1 and ferroptosis”

  • The paper relies on this without support.

    TasQ specifically binds to the Zn2+ domain of HDAC4 and inhibits its interaction with HDAC3 to block downstream target genes regulated by HDAC4.

    “TasQ is believed to have the ability to specifically bind to the Zn2+ domain of HDAC4 and inhibit its interaction with HDAC3 to block the downstream target genes regulated by HDAC4.”

  • The paper relies on this without support.

    Very few drugs are available for the sensitization of lung cancer to radiotherapy.

    “However, thus far, very few drugs are available for the sensitization of lung cancer to radiotherapy.”

  • The paper relies on this without support.

    PROTACs require high affinity to target proteins and the recruitment of E3 ubiquitin ligases to promote target protein ubiquitination, leading to proteasomal degradation.

    “PROTACs require high affinity to target proteins and the recruitment of E3 ubiquitin ligases to promote target protein ubiquitination, leading to proteasomal degradation.”

  • The paper relies on this without support.

    Normal lung organoid sensitivity is a valid indicator of in vivo toxicity.

    “By establishing normal lung-like organs, we found that normal lung organoids were not sensitive to TP1, indicating its low toxicity.”

  • The paper relies on this without support.

    Preclinical findings from cell lines, organoids, and immunodeficient xenograft models can be used in clinical research.

    “These findings suggest that small-molecule compounds can be used in clinical research.”

  • The paper relies on this without support.

    The complex tumor microenvironment and immune responses influence radiotherapy efficacy in patients.

    “which do not completely recapitulate the complex tumor microenvironment and immune responses that influence radiotherapy efficacy in patients.”
10 of 10

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • CYP1A1 overexpression is said to both reverse and increase lipid ROS

    Major

    The Results say CYP1A1 overexpression reversed an increase in lipid ROS, but the Discussion says CYP1A1 overexpression in HDAC4-overexpressing cells increased lipid peroxidation.

  • Claim that all in vitro experiments were repeated conflicts with single-run screen

    Minor

    The Methods state that all in vitro experiments were performed at least three times independently, but the organoid CRISPR screen is explicitly reported as n = 1.

  • CUT&Tag organoid identity differs between text and figure caption

    Minor

    The Results text says MBD1 CUT&Tag sequencing was performed in LCO-4 organoids, while the Fig. 5 caption identifies LCO-1 organoids.

  • HDAC4 mutant is identified by two different residue numbers

    Minor

    The Fig. 2 caption names a D803A&D840N mutant, whereas the accompanying Results text names the deacetylase-inactive mutant H803A, D840N.

4 of 4

Cites

Flagged first, then by citations

2 of the 78 references couldn’t be matched to a known paper.

Authors
Cheng, C., Sun, L., Yang, J., Liu, Z., Zhang, F., Qiu, L., Yu, M., Wang, T., Huang, J., Wang, L., Min, W.-P., Xiang, T., Hu, K., & Sang, Y.
Affiliations
  • Nanchang University (CN)
  • First Affiliated Hospital of Nanchang University (CN)
  • Jiangxi Provincial Cancer Hospital (CN)
  • Shanghai Medical College of Fudan University (CN)
  • Western University (CA)
  • Chongqing University (CN)
  • Sun Yat-sen University (CN)
Corresponding author
  • Xiang, Tingxiu
  • Hu, Kaishun
  • Sang, Yi
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2026-05-25
Volume
17
Issue
1
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-026-73682-0
PMC
PMC13389272
OpenAlex
W7162327739
Semantic Scholar
b0cd1a1786f24631b39f0fc8800d73f386f35068
Cited by
0
References
78
FWCI
0.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
  • National Natural Science Foundation of China (82360474, 82573408, 82373150)
  • Health Commission of Jiangxi Province
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
Keywords
HDAC4, PROTAC degraders, ferroptosis, radioresistance (biology), lung cancer, MBD1, SUMOylation, SUMO E3 ligase, tasquinimod, TP1, lipid peroxidation, TP53, CYP1A1, radiosensitization, post-translational modification, protein degradation
MeSH terms
Ferroptosis, Proteolysis Targeting Chimera, Animals, DNA-Binding Proteins, Histone Deacetylases, Humans, Lung Neoplasms, Organoids, Radiation Tolerance, Radiation-Sensitizing Agents, Repressor Proteins, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Ubiquitination, Proteolysis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-23.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-23.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

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