---
title: "Anwulignan induces pyroptosis and overcomes proteasome inhibitor resistance in multiple myeloma"
id: "pubmed-42704369"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42704369"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42704369/"
doi: "10.1007/s10495-026-02426-8"
published_at: "2026-09-07T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Anwulignan induces pyroptosis and overcomes proteasome inhibitor resistance in multiple myeloma
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42704369
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42704369/)
- **DOI:** [10.1007/s10495-026-02426-8](https://doi.org/10.1007%2Fs10495-026-02426-8)
- **Published At:** 2026-09-07T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- Resistance to **proteasome inhibitors** (PIs) and weak anti-tumor immune engagement limit effective treatment of **multiple myeloma** (MM). - The natural product **anwulignan** was identified as cytotoxic to MM cells, retaining activity in PI-resistant models. - Anwulignan synergized with proteasome inhibitors in both in vitro and in vivo experiments, producing greater tumor suppression than single agents. - In mouse MM models, anwulignan markedly reduced tumor growth while showing acceptable tolerability and safety in the reported experiments. - Mechanistic studies identified **nucleophosmin 1 (NPM1)** as a direct molecular target of anwulignan; NPM1 inhibition induced cell-cycle arrest and apoptosis. - Anwulignan activated a **caspase-1-dependent gasdermin D (GSDMD) pyroptosis** pathway, producing **immunogenic cell death** and engaging anti-tumor immunity. - Genetic silencing of **GSDMD** substantially reduced anwulignan-mediated tumor suppression in vitro and in vivo, indicating pyroptosis is a critical effector mechanism. - In immunocompetent syngeneic MM models, anwulignan increased bone marrow and splenic **T-cell** proportions and achieved better tumor control compared with GSDMD-deficient tumors. - The data support a dual-function therapeutic concept: direct MM cytotoxicity through NPM1 inhibition plus immune activation via **pyroptosis-driven immunogenic cell death**. - These findings provide translational rationale for exploring natural products like anwulignan to target PI-resistant MM and to enhance anti-myeloma immune responses.
## Clinical Analysis & Structured Key Points
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Activating a novel cell death pathway to target PI-resistant multiple myeloma and enhance immunogenic cell death [Xinyun Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+X&cauthor_id=42704369)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42704369/#full-view-affiliation-1 "Department of Hematology, the Second Affiliated Hospital of Soochow University, San Xiang Road 1055, Suzhou, China.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42704369/#full-view-affiliation-2 "Department of Pharmacy, the Second Affiliated Hospital of Soochow University, Suzhou, China."), [Zhiming Wang](https://pubmed.ncbi.nlm.nih.gov/?term=Wang+Z&cauthor_id=42704369)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42704369/#full-view-affiliation-3 "Department of Cell Biology, School of Biology & Basic Medical Sciences, Suzhou Medical College of Soochow University, 215123, Ren Ai Road 199, Suzhou, China."), [Yilei Shi](https://pubmed.ncbi.nlm.nih.gov/?term=Shi+Y&cauthor_id=42704369)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42704369/#full-view-affiliation-1 "Department of Hematology, the Second Affiliated Hospital of Soochow University, San Xiang Road 1055, Suzhou, China."), [Qi Li](https://pubmed.ncbi.nlm.nih.gov/?term=Li+Q&cauthor_id=42704369)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42704369/#full-view-affiliation-1 "Department of Hematology, the Second Affiliated Hospital of Soochow University, San Xiang Road 1055, Suzhou, China."), [Si Chen](https://pubmed.ncbi.nlm.nih.gov/?term=Chen+S&cauthor_id=42704369)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42704369/#full-view-affiliation-4 "Suzhou Sano Precision Medicine Ltd, Suzhou, China."), [Lexin He](https://pubmed.ncbi.nlm.nih.gov/?term=He+L&cauthor_id=42704369)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42704369/#full-view-affiliation-4 "Suzhou Sano Precision Medicine Ltd, Suzhou, China."), [Yali Chai](https://pubmed.ncbi.nlm.nih.gov/?term=Chai+Y&cauthor_id=42704369)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42704369/#full-view-affiliation-3 "Department of Cell Biology, School of Biology & Basic Medical Sciences, Suzhou Medical College of Soochow University, 215123, Ren Ai Road 199, Suzhou, China."), [Hao Xu](https://pubmed.ncbi.nlm.nih.gov/?term=Xu+H&cauthor_id=42704369)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42704369/#full-view-affiliation-1 "Department of Hematology, the Second Affiliated Hospital of Soochow University, San Xiang Road 1055, Suzhou, China."), [Yuchen Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+Y&cauthor_id=42704369)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42704369/#full-view-affiliation-1 "Department of Hematology, the Second Affiliated Hospital of Soochow University, San Xiang Road 1055, Suzhou, China."), [Meifang Zhao](https://pubmed.ncbi.nlm.nih.gov/?term=Zhao+M&cauthor_id=42704369)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42704369/#full-view-affiliation-1 "Department of Hematology, the Second Affiliated Hospital of Soochow University, San Xiang Road 1055, Suzhou, China."), [Wenzhuo Zhuang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhuang+W&cauthor_id=42704369)[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42704369/#full-view-affiliation-5 "Department of Cell Biology, School of Biology & Basic Medical Sciences, Suzhou Medical College of Soochow University, 215123, Ren Ai Road 199, Suzhou, China. zhuangwenzhuo@suda.edu.cn."), [Bingzong Li](https://pubmed.ncbi.nlm.nih.gov/?term=Li+B&cauthor_id=42704369)[ 6 ](https://pubmed.ncbi.nlm.nih.gov/42704369/#full-view-affiliation-6 "Department of Hematology, the Second Affiliated Hospital of Soochow University, San Xiang Road 1055, Suzhou, China. lbzwz0907@hotmail.com.") Affiliations Expand ### Affiliations * 1 Department of Hematology, the Second Affiliated Hospital of Soochow University, San Xiang Road 1055, Suzhou, China. * 2 Department of Pharmacy, the Second Affiliated Hospital of Soochow University, Suzhou, China. * 3 Department of Cell Biology, School of Biology & Basic Medical Sciences, Suzhou Medical College of Soochow University, 215123, Ren Ai Road 199, Suzhou, China. * 4 Suzhou Sano Precision Medicine Ltd, Suzhou, China. * 5 Department of Cell Biology, School of Biology & Basic Medical Sciences, Suzhou Medical College of Soochow University, 215123, Ren Ai Road 199, Suzhou, China. zhuangwenzhuo@suda.edu.cn. * 6 Department of Hematology, the Second Affiliated Hospital of Soochow University, San Xiang Road 1055, Suzhou, China. lbzwz0907@hotmail.com. * PMID: **42704369** * DOI: [ 10.1007/s10495-026-02426-8 ](https://doi.org/10.1007/s10495-026-02426-8) Item in Clipboard # Activating a novel cell death pathway to target PI-resistant multiple myeloma and enhance immunogenic cell death Xinyun Zhang et al. Apoptosis. 2026. Show details Display options Display options Format Abstract PubMed PMID Apoptosis Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Apoptosis%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Apoptosis%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42704369/) . 2026 Sep 7;31(10):225. doi: 10.1007/s10495-026-02426-8. ### Authors [Xinyun Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+X&cauthor_id=42704369)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42704369/#short-view-affiliation-1 "Department of Hematology, the Second Affiliated Hospital of Soochow University, San Xiang Road 1055, Suzhou, China.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42704369/#short-view-affiliation-2 "Department of Pharmacy, the Second Affiliated Hospital of Soochow University, Suzhou, China."), [Zhiming Wang](https://pubmed.ncbi.nlm.nih.gov/?term=Wang+Z&cauthor_id=42704369)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42704369/#short-view-affiliation-3 "Department of Cell Biology, School of Biology & Basic Medical Sciences, Suzhou Medical College of Soochow University, 215123, Ren Ai Road 199, Suzhou, China."), [Yilei Shi](https://pubmed.ncbi.nlm.nih.gov/?term=Shi+Y&cauthor_id=42704369)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42704369/#short-view-affiliation-1 "Department of Hematology, the Second Affiliated Hospital of Soochow University, San Xiang Road 1055, Suzhou, China."), [Qi Li](https://pubmed.ncbi.nlm.nih.gov/?term=Li+Q&cauthor_id=42704369)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42704369/#short-view-affiliation-1 "Department of Hematology, the Second Affiliated Hospital of Soochow University, San Xiang Road 1055, Suzhou, China."), [Si Chen](https://pubmed.ncbi.nlm.nih.gov/?term=Chen+S&cauthor_id=42704369)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42704369/#short-view-affiliation-4 "Suzhou Sano Precision Medicine Ltd, Suzhou, China."), [Lexin He](https://pubmed.ncbi.nlm.nih.gov/?term=He+L&cauthor_id=42704369)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42704369/#short-view-affiliation-4 "Suzhou Sano Precision Medicine Ltd, Suzhou, China."), [Yali Chai](https://pubmed.ncbi.nlm.nih.gov/?term=Chai+Y&cauthor_id=42704369)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42704369/#short-view-affiliation-3 "Department of Cell Biology, School of Biology & Basic Medical Sciences, Suzhou Medical College of Soochow University, 215123, Ren Ai Road 199, Suzhou, China."), [Hao Xu](https://pubmed.ncbi.nlm.nih.gov/?term=Xu+H&cauthor_id=42704369)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42704369/#short-view-affiliation-1 "Department of Hematology, the Second Affiliated Hospital of Soochow University, San Xiang Road 1055, Suzhou, China."), [Yuchen Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+Y&cauthor_id=42704369)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42704369/#short-view-affiliation-1 "Department of Hematology, the Second Affiliated Hospital of Soochow University, San Xiang Road 1055, Suzhou, China."), [Meifang Zhao](https://pubmed.ncbi.nlm.nih.gov/?term=Zhao+M&cauthor_id=42704369)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42704369/#short-view-affiliation-1 "Department of Hematology, the Second Affiliated Hospital of Soochow University, San Xiang Road 1055, Suzhou, China."), [Wenzhuo Zhuang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhuang+W&cauthor_id=42704369)[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42704369/#short-view-affiliation-5 "Department of Cell Biology, School of Biology & Basic Medical Sciences, Suzhou Medical College of Soochow University, 215123, Ren Ai Road 199, Suzhou, China. zhuangwenzhuo@suda.edu.cn."), [Bingzong Li](https://pubmed.ncbi.nlm.nih.gov/?term=Li+B&cauthor_id=42704369)[ 6 ](https://pubmed.ncbi.nlm.nih.gov/42704369/#short-view-affiliation-6 "Department of Hematology, the Second Affiliated Hospital of Soochow University, San Xiang Road 1055, Suzhou, China. lbzwz0907@hotmail.com.") ### Affiliations * 1 Department of Hematology, the Second Affiliated Hospital of Soochow University, San Xiang Road 1055, Suzhou, China. * 2 Department of Pharmacy, the Second Affiliated Hospital of Soochow University, Suzhou, China. * 3 Department of Cell Biology, School of Biology & Basic Medical Sciences, Suzhou Medical College of Soochow University, 215123, Ren Ai Road 199, Suzhou, China. * 4 Suzhou Sano Precision Medicine Ltd, Suzhou, China. * 5 Department of Cell Biology, School of Biology & Basic Medical Sciences, Suzhou Medical College of Soochow University, 215123, Ren Ai Road 199, Suzhou, China. zhuangwenzhuo@suda.edu.cn. * 6 Department of Hematology, the Second Affiliated Hospital of Soochow University, San Xiang Road 1055, Suzhou, China. lbzwz0907@hotmail.com. * PMID: **42704369** * DOI: [ 10.1007/s10495-026-02426-8 ](https://doi.org/10.1007/s10495-026-02426-8) Item in Clipboard Cite Display options Display options Format Abstract PubMed PMID ## Abstract Resistance to proteasome inhibitors (PIs) and inadequate engagement of anti-tumor immunity remain major barriers to effective treatment of multiple myeloma (MM). Here, we identified anwulignan, a bioactive natural product, as a translationally promising agent that retains activity in PI-resistant MM cells and promotes anti-myeloma immune responses. Anwulignan demonstrated potent cytotoxic activity against MM cells and exhibited strong synergy with proteasome inhibitors both in vitro and in vivo. In mouse MM models, anwulignan significantly suppressed tumor growth while maintaining favorable tolerability and safety profiles. Mechanistically, nucleophosmin 1 (NPM1) has been identified as a direct molecular target of anwulignan. Elevated NPM1 expression correlates with poor clinical outcomes in MM, and its inhibition by anwulignan induces cell cycle arrest and apoptosis. In addition to its tumor-intrinsic cytotoxic effects, anwulignan activated the caspase-1-dependent gasdermin D (GSDMD) pyroptosis pathway, thereby inducing immunogenic cell death. Genetic silencing of GSDMD markedly impaired anwulignan-mediated tumor suppression in vitro and in vivo, highlighting pyroptosis as a critical effector mechanism. In immunocompetent syngeneic MM models, anwulignan treatment increased bone marrow and splenic T-cell proportions and achieved superior tumor control compared with GSDMD-deficient tumors. Collectively, these findings establish anwulignan as a dual-function therapeutic that directly targets MM cell survival while simultaneously promoting anti-tumor immunity through pyroptosis-driven immunogenic cell death. This study provides a strong translational rationale for leveraging natural products as immune-engaging strategies to target drug-resistant multiple myeloma and improve therapeutic outcomes. **Keywords:** Anwulignan; Immunogenic cell death; Multiple myeloma; Proteasome inhibitors; Pyroptosis. © 2026. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Conflict of interest statement Declarations. Ethics approval and consent to participate: Animal experiments were approved by the Ethics Committee of Soochow University (Permit Number: SUDA202205A0167). All MM patient samples were collected from the Second Affiliated Hospital of Soochow University after obtaining permission from the Ethics Committee of the Second Affiliated Hospital of Soochow University (Permit Number: JD-LK-2019-068-05). Informed written consent was obtained from each subject or guardian. This study was conducted in accordance with the principles of the Declaration of Helsinki. Consent for publication: All authors have consented to the publication of this manuscript. This manuscript does not contain data from any individual person; therefore, additional consent for publication was not required. Competing interests: The authors declare no competing interests. ## References 1. 1. Malard F et al (2024) Multiple myeloma. Nat Rev Dis Primers 10(1):45 - [DOI](https://doi.org/10.1038/s41572-024-00529-7) - [PubMed](https://pubmed.ncbi.nlm.nih.gov/38937492/) 2. 1. Yang Y et al (2020) Emerging agents and regimens for multiple myeloma. J Hematol Oncol 13(1):150 - [DOI](https://doi.org/10.1186/s13045-020-00980-5) - [PubMed](https://pubmed.ncbi.nlm.nih.gov/33168044/) - [PMC](https://pmc.ncbi.nlm.nih.gov/articles/7654052/) 3. 1. Chari A et al (2019) Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Blood 134(5):421–431 - [DOI](https://doi.org/10.1182/blood.2019000722) - [PubMed](https://pubmed.ncbi.nlm.nih.gov/31113777/) - [PMC](https://pmc.ncbi.nlm.nih.gov/articles/6676132/) 4. 1. Gandolfi S et al (2017) The proteasome and proteasome inhibitors in multiple myeloma. Cancer Metastasis Rev 36(4):561–584 - [DOI](https://doi.org/10.1007/s10555-017-9707-8) - [PubMed](https://pubmed.ncbi.nlm.nih.gov/29196868/) 5. 1. Shah UA, Mailankody S (2020) Emerging immunotherapies in multiple myeloma. BMJ 370:m3176 - [DOI](https://doi.org/10.1136/bmj.m3176) - [PubMed](https://pubmed.ncbi.nlm.nih.gov/32958461/) Show all 38 references ## MeSH terms * Animals Actions * [ Search in PubMed
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