Acta Pharmaceutica Sinica B

CDK9 inhibition sensitizes intrinsically resistant BRAFV⁶⁰⁰E mutant colorectal cancer to BRAF inhibitors

Ning Wei, Natalie Thielen, Mahshid Mohammadi, Muzaffer Ahmed Bhat, Terence Li, Yan Sun, Seiya Kitamura, Edward Chu, Chaoyuan Kuang

Acta Pharmaceutica Sinica B. 2026, 16(8): 5131-5147.

Recently, the BRAF inhibitor (Encorafenib) in combination with Cetuximab and mFOLFOX6 has been approved for the treatment of metastatic CRC (mCRC) patients with BRAF V⁶⁰⁰E mutation in the first line. However, intrinsic resistance to BRAFi still limits its therapeutic efficacy, and the clinical response is only ∼5%. One potential strategy to improve mCRC therapy is to combine agents that target key cellular signaling pathways, which may yield synergistic antitumor efficacy and overcome drug resistance. Herein, CDK9 inhibitors (CDK9i) were identified as candidate synergistic agents through kinase library-based high-throughput screening (HTS) and RNA sequencing. CDK9i synergistically sensitizes the therapeutic efficacy of BRAFi (as well as inhibitors of well-known downstream effector of BRAF, MEK and ERK) in multiple intrinsically resistant CRC models. Notably, CDK9i in combination with BRAFi also resulted in an enhanced therapeutic response in chemo-resistant CRC cells and PDOs. Taken together, CDK9 inhibition overcomes intrinsic resistance to BRAFi monotherapy, and targeting CDK9-mediated transcriptional elongation appears to be a promising and tolerable sensitization strategy for BRAFi-based treatment in mCRC, even in chemo-resistant mCRC.

The role of non-coding RNAs in regulating R-loop dynamics in cancer: Mechanisms and therapeutic implications

Acta Pharmaceutica Sinica B. 2026, 16(8): 4749-4769.

R-loops, RNA:DNA hybrids formed during transcription, play critical roles in regulating gene expression and maintaining genome stability. Dysregulation of R-loop formation and resolution has been linked to genomic instability, a hallmark of cancer. Recent advances have highlighted the pivotal role of non-coding RNAs (ncRNAs), particularly long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), in modulating R-loop dynamics, influencing tumorigenesis, and contributing to therapeutic resistance. These ncRNAs participate in the formation, stabilization, and resolution of R-loops, which in turn regulate critical processes such as transcriptional regulation, DNA repair, and chromatin architecture. For example, circRNAs such as circSMARCA5 and circDMD have been shown to induce R-loop formation, influencing gene expression and sensitizing cancer cells to chemotherapy. Conversely, lncRNAs such as TUG1 and NEAT1 regulate R-loop resolution, maintaining genome stability and enhancing tumor cell survival. The interaction between ncRNAs and R-loops offers promising avenues for targeted therapeutic strategies aimed at restoring R-loop balance to improve cancer treatment outcomes. This review provides an in-depth exploration of the molecular mechanisms by which ncRNAs modulate R-loop dynamics and discusses their potential as biomarkers and therapeutic targets in oncology. Furthermore, we highlight the challenges and future directions in translating these findings into clinical applications.

Formic acid released by intratumoral Bacteroides thetaiotaomicron facilitates combinational therapy of Apatinib and aPD-1 in hepatocellular carcinoma

Jiongjiong Lu, Feiling Feng, Chunlei Li, Ziqing Yu, Tingting Zhang, Anchang Liu, Qingxiang Gao, Zhizhen Li, Li Luo, Xuemei Guan, Yanxiao Xiang, Hao Zhuang

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.

Novel circUnc79 regulates morphine-induced reward memory via the miR-149-3p/EAAT2 axis and glutamatergic plasticity

Xixi Yang, Feifei Gao, Zhuojin Yang, Dongyu Yu, Jie Chen, Zhen Yao, Qi Liao, Jingsi Yang, Junlin Liu, Boyuan Gu, Yuxiang Zhang, Chunxia Yan

Acta Pharmaceutica Sinica B. 2026, 16(8): 5148-5167.

Opioid addiction is driven by maladaptive reward memory, yet its molecular underpinnings remain poorly understood. Circular RNAs (circRNAs) have emerged as key regulators of neuroplasticity, but their roles in addiction-related memory remain unclear. Here, we identify circUnc79, a neuron-enriched and synaptically localized circRNA, as a critical modulator of morphine reward memory in the medial prefrontal cortex (mPFC). In the morphine-induced conditioned place preference (CPP) model, circUnc79 expression is dynamically downregulated during cue-induced memory retrieval. Gain- and loss-of-function experiments demonstrate that circUnc79 bidirectionally regulates the acquisition and persistence of morphine reward memory, without affecting locomotion, anxiety-like behavior, social interaction, or sucrose reward. Mechanistically, circUnc79 acts as a competing endogenous RNA for miR-149-3p, thereby relieving its repression of excitatory amino acid transporter 2 (EAAT2, encoded by Slc1a2). Elevated neuronal EAAT2 enhances presynaptic glutamate reuptake and recycling, supporting reward memory encoding. Manipulation of miR-149-3p produces opposite behavioral and synaptic effects, supporting the functional relevance of this regulatory axis. These findings reveal a circUnc79/miR-149-3p/EAAT2 pathway that regulates synaptic plasticity underlying opioid reward memory and highlight circUnc79 as a potential therapeutic target for opioid use disorders.

HIFs: The central drivers of tumors and their role as molecular switches in targeted therapy?

Acta Pharmaceutica Sinica B. 2026, 16(8): 4808-4828.

Hypoxia-inducible factors (HIFs) serve as the central signaling hub within the hypoxic tumor microenvironment, coordinating tumor proliferation, metastasis, and therapy resistance. This protein family comprises HIF-1α, HIF-2α, HIF-3α, and HIF-1β, with distinct subcellular localization patterns reflecting their isoform-specific oxygen-sensing mechanisms. Tumor-associated HIF expression is regulated through a multifaceted network involving non-coding RNAs (ncRNAs), mitochondrial metabolites, and post-translational modifications (PTMs). These aberrantly expressed HIFs then orchestrate biologically important processes including metabolic reprogramming, angiogenesis, and pro-tumorigenic inflammation. It is important to note that current evidence regarding HIF-3α function remains limited and requires further validation in vivo. This review first systematically deciphers the mechanisms governing HIF dysregulation in tumors, before elucidating the key biological processes involved. We then synthesize advances in HIF-targeting inhibitors. These pivotal findings provide a solid theoretical foundation and novel insights for both anticancer therapies targeting this critical “molecular switch” and translational research focusing on HIFs as promising therapeutic targets.

Metabolic-epigenetic reprogramming via the PLOD1-PFKP axis drives cisplatin resistance in HNSCC

Acta Pharmaceutica Sinica B. 2026, 16(8): 5108-5130.

Cisplatin remains a cornerstone of treatment for head and neck squamous cell carcinoma (HNSCC), yet its therapeutic efficacy is often undermined by acquired resistance. Here, we identify the PLOD1-PFKP-glycolysis axis as a central driver of cisplatin resistance. PLOD1 is significantly upregulated in cisplatin-resistant tumors and correlates with poor prognosis. Mechanistically, PLOD1 stabilizes the glycolytic enzyme PFKP by promoting its AKT-mediated phosphorylation at serine 386 via the HSP90-AKT complex, thereby enhancing glycolytic flux. This metabolic reprogramming facilitates stem-like properties and sustains epithelial-mesenchymal transition (EMT). Furthermore, increased intracellular acetyl-CoA levels driven by this axis promote histone H3K27 acetylation at the TGFBR2 promoter, thereby activating TGF-β signaling. Genetic depletion or nanoparticle-mediated silencing of PLOD1 reverses EMT and stemness features, restores cisplatin sensitivity, and impairs tumor growth and metastasis in vivo. These findings reveal a PLOD1-PFKP-glycolysis axis as the principal driver of cisplatin resistance, which coordinates metabolic and epigenetic alterations to promote tumor plasticity. Targeting this axis offers a promising strategy to overcome chemoresistance in HNSCC.

Nanocarrier-based delivery of Pt(IV) compounds for chemoimmunotherapy and theranostics: Advances, challenges, and prospects

Daniil Spector, Roman Akasov, Vladislav Bykusov, Georgy Karetnikov, Anastasia Zharova, Elena Beloglazkina, Olga Krasnovskaya

Acta Pharmaceutica Sinica B. 2026, 16(8): 4898-4977.

Nanocarrier-based delivery of platinum compounds represents the next generation of platinum-based chemotherapy, which is a first-line treatment for many types of tumors. Despite the significant success of Pt(IV) prodrugs as effective antitumor agents, the therapeutic efficacy of most of the reported prodrugs is limited due to rapid biodegradation in the bloodstream and limited accumulation in the tumor. To overcome these limitations, various types of nanomedicines have been developed as drug delivery systems for Pt(IV) prodrugs, with those demonstrating significantly enhanced antitumor effects due to passive and active tumor targeting, stimulus-responsive drug release, effective synergistic therapy, the ability to induce immunogenic cell death, stimulate native and adaptive immunity, and preventing tumor recurrence. Also, the design of Pt(IV)-based theranostic nanoagents opens up photothermal, fluorescent, and photoacoustic imaging modalities for real-time monitoring of drug delivery and therapeutic response. The ability to harness photocontrolled chemotherapy along with immunotherapy, PDT, and PTT holds immense promise for synergistic anticancer effects. In the present review, we highlighted recent advances in the design of Pt(IV)-based NPs reported in 2022-2025 with the focus on the further development of this fast-growing research area.

Exendin-4 alleviates anxiety-like behaviors in chronic restraint stress mice via regulating BLA GLP-1R/BDNF signaling

Acta Pharmaceutica Sinica B. 2026, 16(8): 5168-5182.

Clinical studies have suggested that exendin-4 (Ex-4) exhibits therapeutic potential for anxiety disorders, yet the molecular mechanisms underlying its efficacy remain largely unclear. Our study demonstrates that Ex-4 at specific doses ameliorates anxiety-like behaviors in mice. Mechanistically, Ex-4 could cross the blood-brain barrier and enter the central nervous system, where it exerts anxiolytic effects by activating glucagon-like peptide-1 receptor (GLP-1R) in the basolateral amygdala (BLA). Anterior dorsal bed nucleus of the stria terminalis (adBNST) as a downstream projection target of BLA neurons. Chemogenomic inhibition of the BLA-adBNST circuit induced anxiety-like phenotypes, which were rescued by Ex-4 treatment. Brain-derived neurotrophic factor (BDNF), a critical neurotrophin implicated in neuropsychiatric disorders including anxiety and depression, was functionally interrogated in this pathway. Furthermore, conditional knockdown of Bdnf in the BLA-adBNST circuit abolished the anxiolytic effects of Ex-4, indicating that the activation of GLP-1R in BLA neurons drives BDNF release into adBNST to mitigate anxiety. Taken together, these studies identify a central mechanism whereby Ex-4 attenuates anxiety-like behaviors by promoting BDNF release in the BLA-adBNST circuit.

Telomere-associated non-malignant pulmonary diseases: Pathogenic mechanisms and therapeutic strategies

Hongyan Zhan, Ruifang Zheng, Yanyan Li, Xinyu Liu, Yujie Shi, Ruxuan Chen, Qi Hou, Hui Huang, Mingbao Lin

Acta Pharmaceutica Sinica B. 2026, 16(8): 4829-4853.

Telomeres and telomerase have been extensively implicated in the cellular processes of aging and inflammation. Recent studies have shown that telomere length (TL), the shelterin complex, and telomerase dysfunction are closely related to non-malignant pulmonary diseases, including interstitial lung diseases (ILD), chronic obstructive pulmonary disease (COPD), and asthma. Short telomere defects with or without mutations in telomere maintenance genes and telomerase are relatively common, affecting the progression of non-malignant pulmonary diseases, explaining disease susceptibility, and revealing clinically relevant manifestations. In this review, we examine the biological characteristics and functions of telomeres and telomerase, and investigate the intricate relationship between changes in TL and mutations in telomerase genes in non-malignant pulmonary diseases after a detailed associated literature review. Subsequently, we focus on the clinical features of non-malignant pulmonary diseases related to dysfunctional telomeres/telomerase, as well as the potential molecular mechanisms underlying these associations, along with the current status of therapeutic interventions. Finally, we delineate current knowledge gaps and transformative opportunities in telomere biology research, with a focus on bridging molecular discoveries to clinical innovations for telomere-associated non-malignant pulmonary diseases, aiming to accelerate the development of precision diagnostic tools and mechanism-based therapeutics.

Nanobodies targeting SARS-CoV-2 variants

Acta Pharmaceutica Sinica B. 2026, 16(8): 4978-4997.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a beta-coronavirus, caused the recent global Coronavirus Disease 2019 (COVID-19) pandemic. Among the virus-encoded proteins, the surface spike (S) protein is critical for viral entry, membrane fusion, and pathogenesis, and its receptor-binding domain (RBD) initiates viral entry by binding to a cellular receptor. This makes the S an important therapeutic target for COVID-19. SARS-CoV-2 mutates frequently, giving rise to five major variants of concern, among which the Omicron variant and its subvariants are less sensitive to current therapeutic antibodies. The first part of this review describes the main protein constituents of SARS-CoV-2 and their functions, the S protein-mediated viral entry and fusion processes, and the main SARS-CoV-2 variants. Nanobodies are single-domain antibodies with high target-binding affinity, strong stability, and low production costs, whose small size facilitates their access to protein regions that are inaccessible to conventional antibodies. Thus, in the second part, we comprehensively review SARS-CoV-2-targeting nanobodies, including those that bind specifically to the RBDs of the S proteins, non-RBD S proteins, and non-S proteins of variants and subvariants of SARS-CoV-2, with the hope that this information will be valuable for the generation of novel SARS-CoV-2-targeting nanobodies with improved potency against COVID-19.