Acta Pharmaceutica Sinica. B | Isoalantolactone induces AML cell pyroptosis by targeting TXNRD1 and enhances anti-PD-1 efficacy

This study reveals the critical role of TXNRD1 in the immunosuppressive microenvironment of acute myeloid leukemia (AML), providing a novel small-molecule intervention strategy for combined immunotherapy in AML. It particularly supports experimental designs targeting the pyroptosis pathway to enhance responses to anti-PD-1 therapy.

 

Literature Overview

The article titled 'Isoalantolactone induces AML pyroptosis and potentiates α-PD-1 efficacy by targeting selenoprotein TXNRD1,' published in Acta Pharmaceutica Sinica. B, systematically investigates the anti-tumor mechanism of the natural compound isoalantolactone (IAL) in acute myeloid leukemia (AML) and its ability to sensitize tumors to immune checkpoint blockade. The study finds that IAL covalently modifies the Sec498 site of TXNRD1, inhibiting its enzymatic activity, subsequently activating the PPARγ/caspase-3/GSDME signaling axis to induce pyroptosis in AML cells. Additionally, IAL upregulates PD-L1 expression, thereby improving the immune microenvironment and enhancing the efficacy of anti-PD-1 therapy. This work provides new insights into overcoming resistance to immunotherapy in AML.

Background Knowledge

Acute myeloid leukemia (AML) is a highly heterogeneous hematologic malignancy, with treatment still challenged by high relapse and drug resistance rates. The AML microenvironment exhibits significant immunosuppressive characteristics, including T-cell exhaustion, expansion of myeloid-derived suppressor cells (MDSCs), and impaired antigen presentation, all of which limit the efficacy of immune checkpoint inhibitors such as anti–PD-1/PD-L1 antibodies. Currently, the regulatory mechanisms of PD-L1 expression are complex, and there remains a lack of effective small-molecule drugs to synergistically enhance targeted therapies. Moreover, TXNRD1, a central regulator of cellular redox homeostasis, is highly expressed in various cancers and associated with poor prognosis, yet its functional role and druggability in AML remain unclear. This study leverages the natural product IAL as a probe molecule to systematically identify its direct target, TXNRD1, and explores its dual role in inducing pyroptosis and reshaping the immune microenvironment, thereby providing mechanistic support for developing 'chemotherapy-immunotherapy' combination strategies.

 

 

Research Methods and Experiments

The authors used multiple AML cell lines (e.g., THP-1) and primary patient-derived cells for in vitro functional validation, and established PDX, CDX, and syngeneic mouse transplantation models for in vivo pharmacological evaluation. Using techniques such as CETSA, ITC, and LC-MS/MS, they demonstrated that IAL directly binds to the Sec498 site of TXNRD1 in a manner dependent on its α,β-unsaturated carbonyl structure, achieving covalent modification via Michael addition. In animal models, IAL significantly suppressed AML cell infiltration in the bone marrow and spleen and prolonged survival. When combined with anti–PD-1 therapy, tumor burden was further reduced, and the immune microenvironment shifted toward a 'hot tumor' phenotype, characterized by increased CD8+ T-cell infiltration and decreased MDSC proportions.

Key Conclusions and Perspectives

• IAL irreversibly inhibits TXNRD1 enzymatic activity by covalently binding to its Sec498 residue—a finding that provides a structural basis for developing covalent inhibitors targeting selenoproteins and guides the optimization of α,β-unsaturated lactone scaffolds in future drug design
• Inhibition of TXNRD1 activates the transcription factor PPARγ, promoting its nuclear translocation and subsequent upregulation of caspase-3, which cleaves GSDME to trigger pyroptosis. This signaling axis reveals a novel mechanism for pyroptosis regulation in AML and suggests PPARγ agonists as potential candidates for combination therapy
• Activation of caspase-3 during pyroptosis promotes PARP-1 cleavage and upregulates PD-L1 expression, thereby increasing AML cell sensitivity to anti–PD-1 treatment. This mechanism provides a theoretical foundation for a sequential therapeutic strategy: inducing immunogenic cell death first, followed by immune checkpoint blockade
• Analysis of clinical samples shows that TXNRD1 is highly expressed in AML patients and correlates with poor prognosis, supporting its potential as an independent prognostic biomarker and therapeutic target. Its predictive value should be validated in future clinical cohorts

Research Significance and Prospects

This study opens a new avenue for targeted therapy in AML, demonstrating that small-molecule–induced pyroptosis can effectively break immune tolerance. As a druggable target, TXNRD1 and its inhibitors—such as IAL or the already approved drug auranofin—have strong potential for rapid clinical translation, particularly for AML patients with low PD-L1 expression or 'cold' immune microenvironments. Future efforts could focus on structural optimization of IAL analogs to improve selectivity and pharmacokinetic properties.

From a drug development perspective, this work supports the strategy of combining pyroptosis inducers with immune checkpoint inhibitors, highlighting the importance of treatment sequencing and dose optimization. Additionally, as a downstream effector, the potential of PPARγ agonists to replace IAL in certain patients warrants further investigation.

 

 

Conclusion

This study systematically elucidates the molecular mechanism by which the natural compound isoalantolactone induces pyroptosis in AML cells and enhances the efficacy of anti–PD-1 therapy by targeting TXNRD1, revealing a critical link between redox regulation and immune microenvironment remodeling. From bench to bedside, this discovery offers a 'dual-effect' therapeutic strategy for AML patients: directly killing leukemia cells while simultaneously releasing inflammatory factors through pyroptosis to activate anti-tumor immunity. As a central node, TXNRD1 not only holds prognostic value but also represents an ideal target for small-molecule intervention. In the future, derivatives based on the IAL structure may propel novel immune-synergistic therapies into clinical trials, potentially overcoming the current challenge of low response rates to AML immunotherapy. This study lays a solid foundation for establishing a new comprehensive intervention framework for AML centered on pyroptosis and combined immunotherapy, holding significant translational medical value.

 

Xiaoxuan Yu, Yanyu Zhou, Shibo Sun, Jianqiang Xu, and Wukun Liu. Isoalantolactone induces AML pyroptosis and potentiates α-PD-1 efficacy by targeting selenoprotein TXNRD1. Acta Pharmaceutica Sinica. B.