Acta Pharmaceutica Sinica B

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Cytoplasmic relocation of nuclear Ku70 by Bruceine A augments cGAS-STING pathway-mediated anti-tumor immunity

Acta Pharmaceutica Sinica B. 2026, 16(8): 5200-5216.

DNA-damaging agents combined with agonists of the cGAS-STING pathway can effectively suppress colorectal cancer (CRC) by inducing cancer cell death and eliciting an antitumor immune response. In this study, we demonstrate that the natural compound Bruceine A (BA) inhibits CRC progression through a dual mechanism involving nuclear-to-cytoplasmic translocation of Ku70. Cytoplasmic Ku70 loses its canonical DNA repair function while simultaneously enhancing its interaction with cGAS, leading to increased cGAS oligomerization and elevated levels of double-stranded DNA (dsDNA), both of which amplify cGAS-STING signaling. Furthermore, Bruceine A-mediated Ku70 translocation exacerbates DNA damage accumulation, further enhancing tumor immunogenicity. In the murine CRC model, Bruceine A significantly inhibited tumor growth and enhanced tumor sensitivity to chemotherapy, radiotherapy, and anti-PD-1 treatment. Notably, genetic ablation of STING and CD8⁺ T cells in mice substantially abolished the antitumor effects of Bruceine A, confirming its reliance on cGAS-STING activation and adaptive immunity. Our findings establish Ku70 as a novel therapeutic target in CRC, where its subcellular redistribution disrupts genomic stability and bridges innate immune activation, synergistically promoting tumor cell death and antitumor immunity. Modulating Ku70 localization thus represents a promising strategy to enhance CRC treatment.
Formic acid released by intratumoral Bacteroides thetaiotaomicron facilitates combinational therapy of Apatinib and aPD-1 in hepatocellular carcinoma

Acta Pharmaceutica Sinica B. 2026, 16(8): 5217-5236.

Through various murine models and 5 R-16 S sequencing, we identified Bacteroides thetaiotaomicron (B.t) as a sensitizer for the combined treatment of Apatinib and anti-PD-1 therapy. Clinically, B.t enrichment was associated with improved neoadjuvant treatment outcomes and a favorable prognosis in HCC patients. Mechanistically, B.t produces formic acid in tumor cells, inhibits aryl hydrocarbon receptor (AhR) nuclear translocation by methylation, and suppresses downstream pathways, thereby mitigating pro-angiogenic effects and immunosuppression. The addition of formate or AhR inhibitors with combined treatment significantly enhanced therapeutic efficacy in preclinical models.
A novel small molecule inhibitor targeting KHSRP methylation suppresses colon cancer progression

Acta Pharmaceutica Sinica B. 2026, 16(8): 5237-5258.

RNA-binding proteins (RBPs) are emerging as crucial regulators in cancer, but the development of therapeutic strategies targeting RBPs remains limited. Here, through chemical proteomics approaches, we identify DIQ01 as a novel small-molecule inhibitor of KH-type splicing regulatory protein (KHSRP), an RBP that is aberrantly hyper-expressed in human tumors and plays an essential role in proliferation, metastasis, and tumor progression. DIQ01 specifically binds to the KH3 and KH4 domains (Phe358 as the key residue) of KHSRP, inhibiting its interaction with mRNAs. Furthermore, the binding of DIQ01 diminishes the PRMT5-mediated arginine methylation of KHSRP, a post-translational modification required for its oncogenic activity. Mechanistically, transcriptomic and proteomic profiling suggested that DIQ01 functionally inactivates KHSRP, triggering destabilization and downregulation of its target PLK1 mRNA. This leads to S-phase arrest, DNA damage, and apoptosis in HCT116 cells. Both in vitro and in vivo studies, including CRC xenograft and patient-derived organoid models, demonstrate that DIQ01 exhibits potent antitumor efficacy with minimal systemic toxicity. Our findings underscore the innovative approach of concurrently targeting the RNA-binding function of an RBP and its post-translational modification, highlighting DIQ01's unique mechanism and significant translational potential as a targeted cancer therapy.
Targeting SIRT6 epigenetically restrains neutrophil hyperplasia and enhances chemotherapeutic efficacy

Acta Pharmaceutica Sinica B. 2026, 16(8): 5259-5275.

Myeloproliferative neoplasms (MPNs) are a group of hematologic malignancies for which current treatment options remain limited, underscoring the urgent need to explore novel therapeutic targets and intervention strategies. Through a high-throughput screen of an epigenetic compound library, we identified the SIRT6 allosteric agonist MDL-800 as a potent suppressor of neutrophil hyperplasia. We established an endogenous sirt6-mutant zebrafish model that develops a myeloproliferative neoplasm (MPN)-like phenotype, with a 64% incidence in adult zebrafish. Mechanistically, Sirt6 was found to regulate neutrophil proliferation in vivo and in vitro by deacetylating histone H3K9 at the c-myb promoter. Sirt6 deficiency led to aberrant proliferation of neutrophils and hematopoietic stem/progenitor cells, whereas Sirt6 overexpression significantly alleviated neutrophil hyperplasia and MPN-related symptoms. Furthermore, the SIRT6 activator MDL-800 enhanced the efficacy of imatinib and reduced neutrophil proliferation in a zebrafish leukemia model. In xenograft mouse models, the combination of MDL-800 and imatinib significantly inhibited leukemia progression and restored drug sensitivity in imatinib-resistant cases. This study establishes the Sirt6-c-Myb axis as a core epigenetic pathway for myeloid homeostasis, providing a novel strategy for simultaneously suppressing neutrophil hyperplasia and enhancing chemotherapeutic efficacy in hematologic malignancies.
Rhynchophylline rewires DLAT lipoylation via conformational control to reverse mitochondrial bioenergetic collapse against dopaminergic neuronal injury

Acta Pharmaceutica Sinica B. 2026, 16(8): 5276-5296.

Parkinson's disease (PD), the second most prevalent neurodegenerative disorder, is characterized by progressive loss of dopaminergic neurons in the substantia nigra. Although the molecular mechanisms of PD remain incompletely understood, mitochondrial dysfunction has emerged as a central pathological driver, highlighting the urgent need for therapies targeting mitochondrial homeostasis. In this study, we demonstrate that rhynchophylline (Rhy), a bioactive alkaloid from Uncaria species, exerts neuroprotective effects by restoring mitochondrial dynamics. Thermal proteome profiling identified dihydrolipoamide acetyltransferase (DLAT) as a direct target of Rhy. Genetic ablation of DLAT induced mitochondrial fragmentation and abolished Rhy-mediated beneficial effects on mitochondrial structure and function. Mechanically, Rhy binds to the N-terminal lipoyl domain of DLAT, allosterically disrupting its interaction with sirtuin 4 (SIRT4) and subsequently enhancing DLAT lipoylation, a critical post-translational modification for mitochondrial energy metabolism. In vivo, Rhy administration ameliorated motor deficits and dopaminergic neurodegeneration in both the 6-OHDA-induced and A53T α-synuclein transgenic PD mouse models. Single-nucleus RNA sequencing further highlighted the clinical relevance of DLAT dysregulation in PD. Collectively, our findings establish Rhy as a promising PD therapeutic candidate and delineate DLAT as a pivotal node in therapeutic targets by promoting mitochondrial fusion and bioenergetics, offering a novel mechanistic avenue for neuroprotection.
IFI30 reprograms glioblastoma-associated macrophage and induces immune evasion by MAFF/PTGS2 pathway

Acta Pharmaceutica Sinica B. 2026, 16(8): 5297-5311.

In recent years, immunotherapy has shown obvious advantages in treating cancers. The close interaction between cancer cells and immune cells in the tumor microenvironment (TME) underlies the progression of glioblastoma multiforme (GBM). However, there are no effective immune-related targets against GBM. Here, in silico analyses and experimental data showed that Interferon Gamma Inducible Protein 30 (IFI30), modulated by histone modifications both H3K4me3 and H3K27ac, was up-regulated in GBM and had a potential role in the antitumor immune responses. In vitro and in vivo experiments further revealed that IFI30 modulated the infiltration of tumor-associated macrophages (TAMs) and reduced the proportion of CD8⁺ T cells. Mechanistically, IFI30 induced PGE2 expression in GBM cells via the MAFF/PTGS2 pathway, and PGE2 bound to macrophage EP2/EP4, activating the downstream ERK1/2 and KLF4/STAT6 pathways, stimulating the infiltration of TAMs. Taken together, we characterized the role and mechanisms of IFI30 in the malignant progression of GBM by regulating TAMs, highlighting that IFI30 may benefit GBM patients as a therapeutic target.
Neutralizing dentin sialophosphoprotein facilitates tumor vascular normalization in colorectal cancer by blocking the crosstalk between tumor cells and endothelial cells

Chaoqun Liu, Rui Zhou, Weiwei Liu, Rui Li, Jun Xiao, Jianghua Wu, Ziyan Ning, Zilin Chen, Cheng Qian, Yujie Zhang, Wandie Lin, Liang Zhao

Acta Pharmaceutica Sinica B. 2026, 16(8): 5312-5327.

Irregular, curved, and uneven shapes of tumor vessels contribute to a malignant microenvironment, promoting metastasis. In this study, using patient-derived xenograft models, we observed that tumors derived from metastatic colorectal cancer (CRC) tissues exhibited increased vascular density, hypoxia, and permeability, but reduced perfusion and pericyte coverage, compared with tumors derived from non-metastatic CRC tissues. We conducted a high-throughput microarray analysis to determine the molecular mechanisms underlying compromised vessel structures. Dentin sialophosphoprotein (DSPP) was identified as the most upregulated gene in metastatic CRC with abnormal vasculature. Clinically, high DSPP expression is strongly correlated with poor prognosis and advanced CRC stages. DSPP stimulates tumor vessel abnormalization and CRC metastasis in vivo, and acts as a novel ligand of alpha(v)beta (3) integrin (αvβ3), which is predominantly expressed in tumor vessels. DSPP could directly bind to the peptide segment (amino acids 368-411) of αvβ3 on the cytoplasmic membrane of endothelial cells, activating the mitogen-activated protein kinase signaling pathway. Subsequently, therapeutic targeting of DSPP with human DSPP antibody or TFA, a selective inhibitor of the αvβ3, was investigated to effectively induce tumor vessel normalization and suppress tumor metastasis in mice. Additionally, interleukin-17 F (IL-17F) was identified as an upstream regulator of DSPP expression, which promotes DSPP transcription via p65 binding to its promoter. Therefore, targeting the DSPP/αvβ3 axis to promote tumor vessel normalization and inhibit tumor metastasis represents a new strategy for the clinical implementation of combination targeted therapies in patients with advanced CRC.
Targeting NAT10 with Remodelin reshapes the pro-fibrotic microenvironment in renal fibrogenesis via inhibiting exosome oversecretion from tubular cells

Acta Pharmaceutica Sinica B. 2026, 16(8): 5328-5350.

Renal fibrosis induces irreversible renal failure and lacks therapies. The tubular epithelial cells (TEC) largely depend on exosomes to create a pro-fibrotic microenvironment, initiating fibroblast activation. However, how exosome secretion of TEC is over-activated during renal fibrogenesis remains unknown. Herein, in vitro high-throughout screen uncovered acetyltransferase NAT10 as promising target to interfere with TEC-fibroblast communication. Further experiments showed that NAT10 was upregulated mainly in the TEC of fibrotic kidneys, and its conditional depletion in TEC alleviated renal fibrosis in vivo. Mechanistically, nuclear NAT10 coordinated with cytoplasmic NAT10 to promote exosome secretion of TEC to induce fibroblast activation via combining mRNA ac4C modification and lysine acetylation (Kac). Moreover, NAT10 upregulated the abundance of exosomal Gli in TEC, which were vital for fibroblast activation. In summary, NAT10-mediated orchestration of ac4C and Kac modifications is the mechanism of over-activated exosome secretion of TEC during renal fibrogenesis. And targeting NAT10 with Remodelin is a promising therapy for renal.
Design, preclinical evaluation, and multicenter phase 1 clinical study of HZ-A-018 for relapsed or refractory central nervous system lymphoma

Shenglan Li, Jialiang Lu, Zhuang Kang, Haiyan Yang, Wenbin Qian, Xi Chen, Xianggui Yuan, Miao Hu, Qiuqiu Shi, Xinglu Zhou, Feng Chen, Xiaowu Dong, Wenbin Li

Acta Pharmaceutica Sinica B. 2026, 16(8): 5351-5362.

Effective therapy for relapsed or refractory central nervous system lymphoma (r/r CNSL) remains an unmet medical need. Meanwhile, developing antitumor drugs for CNS malignancies faces the dual challenge of achieving effective blood‒brain barrier (BBB) penetration and potent tumor cell killing. To address these challenges, a comprehensive predictive system was established to support decision-making during the discovery of HZ-A-018, a potent and BBB-permeable Bruton tyrosine kinase (BTK) inhibitor. This study further presents key preclinical results for HZ-A-018, as well as efficacy/safety data from a multicenter Phase 1 trial in r/r CNSL patients. HZ-A-018 demonstrated manageable safety, with only 19.2% of patients experienced grade 3 or higher adverse events according to the Common Terminology Criteria for Adverse Events version 5.0. Treatment with HZ-A-018 at the recommended phase II dose (RP2D) of 600 mg achieved an overall response rate (ORR) of 72.7% (95% CI, 39.0-94.0) and a 12-month survival rate of 90.5%. The Center for Drug Evaluation in China has authorized the initiation of this single-arm Phase II study as a pivotal registrational clinical trial for accelerated approval of HZ-A-018 for monotherapy in patients with r/r PCNSL. This trial has been registered under the identifiers ChiCTR2400091821 at www.chictr.org.cn and CTR20210181 at www.chinadrugtrials.org.cn.
Novel noscapine derivative induces AML differentiation by dual-engaging DHODH and mitochondrial lipids to trigger a metabolic-epigenetic-transcriptional cascade

Acta Pharmaceutica Sinica B. 2026, 16(8): 5363-5382.

Acute myeloid leukemia (AML) is a heterogeneous and devastating hematologic malignancy characterized by differentiation blockage and immature progenitor accumulation, positioning differentiation therapy as a promising therapeutic strategy. However, clinical success is largely confined to acute promyelocytic leukemia (APL) and isocitrate dehydrogenase (IDH)-mutated AML, leaving most AML subtypes with unmet needs. Herein, novel noscapine derivative ES428 is discovered that induces AML differentiation and exhibits potent anti-AML efficacy across diverse AML cell lines, primary patient samples, as well as cell line- and patient-derived xenograft models. Target deconvolution with combinatorial strategies identifies dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme in de novo pyrimidine synthesis, as the direct functional target. Integration of molecular dynamics simulations and comprehensive structure-activity relationship studies elucidates ES428’s unique mechanism via simultaneous engagement with DHODH and mitochondrial membrane lipids. This dual-engagement underpins ES428’s enhanced target engagement, efficacy, and selectivity in physiologically relevant mitochondrial membrane environment, potentially through stabilizing ES428-DHODH interaction in situ and facilitating ES428’s selective mitochondrial localization. Furthermore, ES428 triggers a mechanistic cascade linking decreased pyrimidine synthesis, reduced O-linked N-acetylglycosylation (O-GlcNAcylation), EP300/CREBBP catalytic inhibition, and transcriptional reprogramming. Our findings identify promising lead candidates, establish a novel DHODH-targeting strategy, and provide important mechanistic insights to advance differentiation therapies for myeloid malignancies.

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