Acta Pharmaceutica Sinica B

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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.
Ginsenoside Rg1 alleviates post-ischemic stroke neuroinflammation by inhibiting CKLF1-mediated suppression of dead/dying neuron clearance

Pinglong Fan, Yuan Ruan, Kaichao Hu, Hongyun Wang, Junrui Ye, Shasha Wang, Ruolan Yuan, Guangyi Yang, Fangmin Liu, Wenbin He, Gang Li, Xu Yan, Shifeng Chu, Zhao Zhang, Naihong Chen

Acta Pharmaceutica Sinica B. 2026, 16(6): 3632-3654.

The reduction of dead/dying neurons represents a critical mechanism for the anti-acute ischemic stroke (AIS) effect of Panax notoginseng, however, its molecular basis remains unclear. Recent findings implicate chemokine-like factor 1 (CKLF1) as a key contributor to the impaired clearance of dying neurons. Here, we established an integrated high-throughput screening strategy combining biolayer interferometry (BLI), liquid chromatography-tandem mass spectrometry (LC-MS/MS), and NanoBRET technologies to identify CKLF1 inhibitors among Panax notoginseng saponins (PNS). Of note, ginsenoside Rg1 (GRg1) exhibits the highest affinity for CKLF1 and the most potent inhibitory efficacy against the CKLF1-CCR4 interaction, effectively suppressing CKLF1-C27 peptide-induced calcium influx and cytokine production. In experimental AIS models, GRg1 confers neuroprotective properties by mitigating ischemic brain damage and promoting neuronal functional recovery. Mechanistically, GRg1 binds to CKLF1 and modulates the mTORC1/TFEB pathway, enhancing lysosomal function and thereby facilitating the clearance of dead/dying neurons. This study presents an efficient approach for the discovery of natural CKLF1 inhibitors and highlights GRg1 as a promising therapeutic candidate for enhancing the clearance of dead/dying neurons in AIS.
Steroid hormone ouabain cooperates with Na⁺,K⁺-ATPase to improve innate immunity against bacterial infections through a non-classic training mechanism regulated by mRNA reprogramming

Lili Chen, Kuida Chen, RunRun Shan, Jinjun Bian, PeiPei Jin, Hao Lin, Jian Liu, Yan Chen, Siyao Zhu, Fangzhou Yin, Wu Yin

Acta Pharmaceutica Sinica B. 2026, 16(6): 3655-3679.

Epigenetic reprogramming underpins trained immunity (TRIM). However, the importance of mRNA reprogramming in TRIM remains unknown. Here, we discovered, for the first time, that the steroid hormone ouabain creates a significant training effect on peripheral innate immune cells (IICs), leading to functional enhancement of IICs against bacterial infections. However, unlike conventional training mechanisms, ouabain primarily relies on an integrated posttranscriptional RNA regulon complex (IPRRC) to establish immune memory and reprogram cytokine expression, with lncRNA-CYTOR playing a critical role in this process. Moreover, to enhance training effects while reducing lactate production, ouabain promotes a rapid degradation of the Na⁺,K⁺-ATPase receptor. Pathologically, endogenous ouabain is downregulated in sepsis-induced immunoparalysis in vivo, correlating with impaired innate immunity. Exogenous ouabain rescue significantly reverses this impairment, and its effect is superior to β-glucan, even when used at one percent of β-glucan dosage. Notably, posttranscriptional RNA regulons are also critically involved in β-glucan’s training effects. Overall, mRNA reprogramming emerges as a new mechanism for TRIM; steroid hormone ouabain is a novel innate immunity regulator.
Syringin disrupts the DLAT/MYC axis to dampen TAM polarization and suppress hepatocellular carcinoma progression

Acta Pharmaceutica Sinica B. 2026, 16(6): 3680-3697.

Tumor-associated macrophages (TAMs) are pivotal drivers of hepatocellular carcinoma (HCC) progression, and blocking TAM M2 polarization has the potential to dampen tumor microenvironment remodeling. In this study, we screened a series of phenylethanoid and phenylpropanoid glycosides and identified syringin as a natural compound capable of inhibiting M2 polarization while promoting M1 polarization in macrophages. Single-cell RNA sequencing confirmed that syringin reduced TAM M2 polarization and significantly impaired tumor microenvironment remodeling. In detail, syringin indirectly reduced the stability of MYC proto-oncogene protein (MYC), which is required for driving a broad set of targets, including Arg1, Il10, Ym1, Mrc1, and Cd274. Using affinity-based protein profiling (ABPP), we revealed dihydrolipoamide S-acetyltransferase (DLAT) as a direct target of syringin. DLAT possesses protein acetyltransferase activity that acetylates MYC at K148. Syringin bound DLAT at residues R430 and N576 and disrupted the DLAT/MYC axis, thereby blocking MYC acetylation and promoting the ubiquitination and degradation of MYC protein. Additionally, syringin enhanced the efficacy of programmed cell death protein 1 blockade in mouse and patient-derived xenograft models, offering a potential adjunctive agent for HCC.
(+)-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.
Primulagenin A is a potent inverse agonist of the nuclear receptor RAR-related orphan receptor gamma (RORγ)

Acta Pharmaceutica Sinica B. 2026, 16(6): 3746-3763.

Throughout history, herbal medicines and natural products have played a crucial role as therapeutics for humans, yet their molecular mechanisms of action often remain elusive. Here, we investigate whether primulagenin A (PGA) from the traditionally used herbal substance Primula root acts via the nuclear receptor RORγ, a key regulator of pro-inflammatory Th17 cells, which are linked to autoimmune diseases like psoriasis. Full-length luciferase assays revealed a high potency (IC₅₀ = 119 nmol/L) and efficacy (Imax = 87%) of PGA as an inverse agonist of RORγ. To ensure sufficient supply, we established methods to isolate and synthesize PGA. Its binding to the human RORγ ligand binding domain was confirmed by nano differential scanning fluorimetry, and a structure-activity relationship was proposed by docking and site-directed mutagenesis. qPCR revealed PGA-mediated downregulation of RORγ target gene expression. Furthermore, PGA inhibited murine and human Th17 differentiation in a concentration-dependent manner and reduced the proportion of IL-17A-producing Th17 cells, as assessed by flow cytometry. In this work, we identify PGA as a new, potent, and efficacious inverse agonist of RORγ, with potential for modulating immune responses in inflammatory and autoimmune diseases.
Lactate metabolism and epigenetic reprogramming drive c-KIT hyperactivation to mediate Gilteritinib resistance: Rationale for c-KIT degraders over kinase inhibitors

Yanli Zhao, Yubo Wang, Ning Liu, Yijie Yang, Jialu Li, Ziqi Huang, Lan Ma, Shuang Yang, Shuangwei Liu, Jingfeng Zhou, Guang Yang

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.
VPS34 inhibition as a host-targeting anti-coronaviral strategy: Rational design of YBM with optimized pharmacokinetic parameters

Acta Pharmaceutica Sinica B. 2026, 16(6): 3784-3801.

Targeting host factors critical to the viral life cycle instead of direct viral enzyme inhibition represents a promising alternative strategy for developing broad-spectrum antivirals. Here, we identified VPS34, a key regulator of autophagosome-lysosome fusion and membrane trafficking, as a conserved host-dependency factor across coronaviruses. VPS34 gene knockdown significantly attenuates viral replication both in vitro and in vivo. Crucially, this antiviral effect remained potent against emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, demonstrating that VPS34 is a drug target resilient to viral evolution. Based on the scaffold structure of the VPS34 inhibitor SAR405, we developed YBM, a novel small-molecule inhibitor, via critical group substitutions and aliphatic chain introduction. YBM exhibited superior pharmacokinetic properties than SAR405, including enhanced bioavailability and prolonged plasma half-life. YBM shows significant in vivo efficacy against SARS-CoV-2 and HCoV-OC43. Crucially, its broad-spectrum potential is underscored by potent in vitro activity against multiple coronavirus genera (α and γ). This study established YBM as a host-targeting antiviral (HTA) that targets VPS34, offering protection against both extant and evolving coronaviruses. The evolutionarily conserved role of VPS34 in mediating coronavirus replication suggests that this host factor may become a priority therapeutic target for coronaviruses during future pandemics.
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.

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