Acta Pharmaceutica Sinica B

Discovery of sulfonyl benzoic acid derivatives with joint TGR5-agonist and FXR-antagonist activity for myocardial ischemia/reperfusion injury protection

Acta Pharmaceutica Sinica B. 2026, 16(6): 3802-3827.

TGR5 and FXR are key regulators of metabolic homeostasis and cardiovascular health. Since the cardioprotective capacity of TGR5 activation and FXR inhibition has been recognized, dual modulation of these targets offers a promising therapeutic strategy for myocardial ischemia/reperfusion injury. Herein, sulfonyl benzoic acid derivatives were identified as effective bidirectional modulators, with compound E6 emerging as a potent lead compound. E6 demonstrated robust dual-target activity, significantly preserving cardiomyocyte viability and attenuated reactive oxygen specie overproduction in hypoxia/reoxygenation models. Moreover, oral administration of E6 markedly reduced infarct size and improved cardiac contractile function after ischemia/reperfusion in vivo, without inducing gallbladder-related side effects. Notably, E6 demonstrated superior efficacy in restoring systolic function compared to mono-regulators. Transcriptomic analysis and subsequent validation studies suggested that its therapeutic effects are mediated through favorable modulation of inflammatory response, attenuation of apoptosis, and enhanced cardiomyocytes survival. Our findings underscore the therapeutic advantages of dual TGR5/FXR targeting and establish E6 as a promising bifunctional lead compound for the treatment of myocardial ischemia/reperfusion injury.

Microneedle technology integrated with diverse therapeutic modalities for hair regrowth in alopecia

Acta Pharmaceutica Sinica B. 2026, 16(6): 3400-3424.

Alopecia profoundly impacts an individual’s appearance, quality of life, and social well-being, with its prevalence increasing with age. Conventional treatments, such as topical minoxidil and oral finasteride, suffer from limitations like inefficient drug delivery, side effects, and inconsistent efficacy. Other therapies, like hair transplantation, biologics and low-level laser therapy (LLLT), also face some constraints in practical application. Microneedles (MNs), as an emerging transdermal drug delivery system (TDDS), enable efficient local delivery of therapeutic agents to hair follicles in the balding scalp by physically penetrate stratum corneum. Through enhanced drug permeability and activation of follicular regeneration pathways, MN-combined strategies have ignited considerable research interest. This review outlines the advances in MN-mediated alopecia treatments over the past five years and underscores their potential to enhance hair regrowth efficacy, including MN-assisted delivery of chemical drugs, natural compounds, biologics, nanomedicines, stem cells, and LLLT. Additionally, this review also summarizes the advances in clinical trials of MN-combined therapies for alopecia over the past five years, highlighting the noticeable disconnection in research focus between basic research and clinical trials. In summary, this review aims to provide critical insights and future perspectives for the development of MN-integrated therapies for alopecia management.

(+)-Miliusol suppresses the Warburg effect and induces regulated cell death in triple-negative breast cancer through targeting EIF3D and remodeling cancer metabolism

Acta Pharmaceutica Sinica B. 2026, 16(6): 3698-3728.

Triple-negative breast cancer (TNBC) exhibits marked molecular heterogeneity, posing ongoing therapeutic challenges. Metabolic reprogramming, particularly through the Warburg effect, offers a promising therapeutic target for TNBC treatment. Data mining and machine learning identified (+)-miliusol as a promising candidate. Its direct target, eukaryotic initiation factor 3D (EIF3D), was validated through mass spectrometry-coupled cellular thermal shift assay (MS-CETSA), a biotinylated probe, and a proteolysis-targeting chimera (PROTAC) approach. EIF3D, an emerging oncoprotein and atypical translation initiation regulator, promotes tumor survival by selectively modulating protein synthesis. (+)-Miliusol demonstrates potent anti-proliferative and anti-migratory activity against TNBC in both in vitro and in vivo. Integrated proteomic and transcriptomic analyses revealed that (+)-miliusol suppresses TNBC progression through EIF3D-mediated translational regulation. Mechanistically, it disrupts the EIF3D-AlkB homolog 5 (ALKBH5)-glucose transporter type 4 (GLUT4) axis, EIF3D-HIF1α signaling, and the EIF3D-RuvB like AAA ATPase 1 (RUVBL1)-β-catenin pathway, thereby inhibiting glycolysis and metastasis while inducing ER stress-dependent apoptosis via caspase-12 and JNK activation. Additionally, (+)-miliusol blocks EIF3D-HIF1α and EIF3D-ALKBH3 interactions, impairing ATAD2/PAK1-regulated Warburg-effect networks and triggering autophagy-associated cell death. (+)-Miliusol induces TNBC cell death by selectively suppressing translation of critical glycolytic and metastatic regulators. These findings establish EIF3D-mediated translational control as a promising therapeutic avenue for TNBC treatment.

NFYB–lncRNA axis resets the tumor microenvironment to promote HCC aggressive progression by a positive feedback loop

Acta Pharmaceutica Sinica B. 2026, 16(6): 3729-3745.

Metastases are a primary cause of cancer-associated mortality; however, the mechanisms underlying aggressive progression have not been clearly elucidated. Genome-wide features of chromatin accessibility through ATAC-seq from HCC primary and metastatic tumors revealed that many distal regulatory elements spreading the genome become accessible during aggressive progression, the changes of which are associated with NFY-family. And NFYB is frequently upregulated in tumor with metastasis. Mechanistically, LINC01137 recruits SMYD3 to enhance H3K4me3 occupancy at IL-1β, CXCL2 and CCL20 promoters by inhibiting lysine ubiquitination to stabilize NFYB, which in turn upregulates IL-1β, CXCL2 and CCL20. HCC-derived cytokine transforms macrophages to the M2 phenotype to foster an inhibitory tumor microenvironment and anti-PDL1 tolerance. Importantly, LINC01137 transcription is activated by the NFYB/KAT2B complex in a feed-forward loop. Notably, treatment with an IL-1β inhibitor enhances the blockade efficacy of PD-L1 in NFYB-overexpressing HCC. Our findings imply an immunosuppressive role of NFYB-LINC01137 signaling during aggressive HCC progression and support the concept of microenvironment engineering in immunotherapy.

Structural characterization of emulsion-type cataplasms with cross-linked networks and systematic establishment of structural parameters

Acta Pharmaceutica Sinica B. 2026, 16(6): 3828-3845.

Compared with conventional cataplasms, those incorporating a cross-linked network structure significantly enhance their mechanical strength and cohesion, endowing them with good formability and adhesion properties, solving problems such as cold flow and slippage, thereby greatly increasing the convenience of use. However, systematic studies investigating the structural profiling of cross-linked networks in cataplasms remain scarce, limiting a comprehensive understanding of their functional significance. Therefore, we developed a systematic methodology to characterize emulsion-type cataplasms (as a model formulation) with cross-linked network structures, classifying their key structural parameters into four levels. The primary structures defined formability and adhesion, ensuring intact and durable skin adhesion. The secondary structure was intermediates formed by the drug and oily components. The tertiary structure was a dynamic structure, evaluating the quality changes of cataplasms during processes such as crosslinking and storage. The quaternary structure was a molecular structure, representing the mechanism by which the cross-linked network structure was formed. The factors influencing structural parameters and the laws between the intrinsic structures were investigated. Furthermore, we established threshold values for the primary structures, indicating when cataplasms possess optimal formability. This study offers new insights for cataplasm design and provides valuable references for industrial development.

Lactate metabolism and epigenetic reprogramming drive c-KIT hyperactivation to mediate Gilteritinib resistance: Rationale for c-KIT degraders over kinase inhibitors

Acta Pharmaceutica Sinica B. 2026, 16(6): 3764-3783.

Kinase inhibitors targeting FLT3-ITD, such as Gilteritinib, have emerged as promising targeted therapies. However, recent clinical trials have shown disappointing overall survival (OS) outcomes in acute myeloid leukemia (AML) patients, primarily due to disease recurrence following treatment. We uncovered a potential mechanism underlying Gilteritinib resistance. Gilteritinib treatment induced reprogramming of lactic acid metabolism in AML cells, leading to increased H3K27 lactylation that continuously amplified c-KIT expression and signaling in AML cells. This mechanism enriched leukemia stem cells (LSCs), driving drug resistance and disease relapse. Notably, c-KIT kinase inhibitors failed to effectively counteract the progression of relapsed and refractory AML, as c-KIT overexpression results in amplification of its signaling. To address this issue, a dual degrader targeting both FLT3-ITD and c-KIT was identified. Beyond exhibiting stronger efficacy than Gilteritinib in inhibiting AML cell proliferation, this PROTAC also demonstrates a significant ability to induce cell differentiation. In cell line-derived xenograft (CDX) models, the degrader significantly suppressed FLT3-ITD⁺ AML recurrence and prolonged the survival of experimental mice. Furthermore, in PDX model established using AML cells from Gilteritinib-resistant patients, the degrader showed significantly superior therapeutic efficacy compared to the combination treatment of Gilteritinib and Imatinib. As a candidate drug molecule, this degrader exhibits promising potential for clinical translation.

Systematic review on genetic polymorphisms associated with idiosyncratic drug-induced liver injury (iDILI): iDILInet as an interactive visualization tool

Acta Pharmaceutica Sinica B. 2026, 16(6): 3603-3631.

Idiosyncratic drug-induced liver injury (iDILI) is a rare, dose-independent and unpredictable adverse reaction occurring at therapeutic drug exposure, and it presents a significant challenge for drug development and patient safety. Despite extensive research, genetic susceptibility to iDILI remains poorly understood. We conducted a comprehensive systematic study of 139 human genetic studies to identify and characterize genetic polymorphisms associated with increased risk or protection against iDILI. Our study included candidate gene studies and genome-wide association studies (GWAS), encompassing 83 risk and 25 protective genes, with NAT2, HLA-B, and SLCO1B1 among the most frequently reported. We performed functional enrichment analyses using KEGG and Gene Ontology, revealing key biological pathways related to immune response, xenobiotic metabolism, and bile secretion. To enhance data accessibility and interpretation, we developed iDILInet, a publicly available web application that enables interactive exploration and network-based visualization of iDILI-associated gene-variant-drug relationships, enriched with liver-specific expression data from the Human Protein Atlas (HPA). Our work provides a novel integrative resource that supports ongoing efforts in precision medicine and pharmacogenomics and represents a significant advancement in implementing living systematic reviews in toxicogenomics.

A lymph node-targeted cell-nanoadjuvant conjugate enhances dendritic cell-T cell crosstalk for cancer immunotherapy

Acta Pharmaceutica Sinica B. 2026, 16(6): 3876-3891.

Dendritic cell (DC) vaccines represent a promising immunotherapeutic strategy by eliciting potent anti-tumor immunity. However, their clinical application remains limited due to poor lymph node (LN) targeting and inadequate T cell activation. Here, we developed an LN-targeted cell-nanoadjuvant conjugate by click-chemistry conjugation of anti-PD-1 antibodies (αPD-1) and Resiquimod (R848) liposomes to DC vaccines (DCVs) (DCV-αPD-1/Lipo) to enhance DC-T cell crosstalk for cancer immunotherapy. DCV-αPD-1/Lipo maintains higher co-stimulatory molecule expression and antigen presentation with enhanced LN targeting efficiency than conventional DC vaccines. The surface-conjugated αPD-1 increases DC-T cell adhesion by 4.97-fold while amplifying the IFN-γ/IL-12 positive feedback loop, thereby potentiating T cell activity and augmenting effector T cells and other immune cells mediated anti-tumor efficacy. This multifunctional integration of adaptive DC therapy, nanoadjuvants and checkpoint blockade establishes an effective approach for next-generation DC therapy.

Advanced drug delivery platforms targeting cellular senescence: A promising strategy for cancer therapy

Acta Pharmaceutica Sinica B. 2026, 16(6): 3473-3505.

Cellular senescence is a state of cell cycle arrest caused by various types of stress, and it is characterized by morphological changes, metabolic reprogramming, and the release of the senescence-associated secretory phenotype (SASP). In cancer therapy, senescence plays a complex role by inhibiting cancer progression, mediating metabolic imbalance, modulating local immune responses, and restructuring the cancer microenvironment. These mechanisms have been harnessed to develop nano-drug delivery systems (Nano-DDSs)-based combination therapies for cancer. We systematically explain key biological features of cellular senescence and detail recent advances in creating drug delivery systems aimed at targeting cancer senescence through these four mechanisms. Additionally, we discuss the clinical challenges in translating senescence-targeting strategies with Nano-DDSs and propose future directions within an interdisciplinary framework. This review offers valuable insights into designing advanced Nano-DDSs based on the multidimensional regulatory mechanisms of cellular senescence and their application in cancer treatment.

Smart responsive hydrogels combined with AI design for tumor therapy

Acta Pharmaceutica Sinica B. 2026, 16(6): 3425-3472.

Advances in cancer therapy have underscored the critical need for multifunctional platforms that enable precise targeting, controlled drug release, and immunomodulation. Hydrogels, as transformative tools with programmable drug release capabilities, microenvironmental responsiveness, and immunoregulatory properties, demonstrate broad application prospects. This review focuses on the design and application of functionalized hydrogels, emphasizing their responsiveness to multiple stimuli, including temperature, pH, reactive oxygen species (ROS), and enzymes. It provides an in-depth analysis of their multimodal synergistic therapeutic mechanisms, including photothermal therapy, immunotherapy, starvation therapy, intelligent detection, targeted capture, and tumor microenvironment (TME) simulation. Meanwhile, recent developments in machine learning-enabled intelligent hydrogel technologies have driven the transformation of materials into intelligent systems with “smart design-perception-decision” capabilities. Although the literature on smart hydrogels has made significant progress in exploring mechanisms and optimizing performance, systematic reviews of artificial intelligence (AI)-driven platforms remain notably lacking. This paper systematically summarizes the regulatory strategies of material-derived intelligent hydrogels, AI-enabled mechanisms, and practical application cases, revealing core challenges and future development directions, thereby providing theoretical guidance and practical pathways for next-generation hydrogels in personalized and multimodal cancer therapy.