Acta Pharmaceutica Sinica B

Home Latest Articles

Latest Articles

Neg-entropy is the true drug target for chronic diseases

Acta Pharmaceutica Sinica B. 2026, 16(1): 231-238.

Molecular mechanisms of chronic diseases are complicated, and it impedes drug target identification and subsequent drug discovery. We consider entropy increase in human body the root causes of chronic diseases. Accordingly, the inherent neg-entropic mechanisms, for instance the homeostatic mechanisms for metabolism, immunity, self-healing, etc., are true drug targets. Only very few molecules (such as proteins) are decisive for neg-entropy related functions, thus they are termed “head goose molecules” (HGMs) here. Identification of HGMs is key to activating neg-entropic mechanism(s), and drug intervention of the HGMs’ functions might reprogram the disease process through a neg-entropy mediated drug cloud (dCloud) effect, resulting in a treatment of both symptoms and root causes of the diseases. Thus, we recommend, for the first time, the “HGMs-neg-entropy-dCloud” axis as an important strategy for discovering new drugs. Clinically proven effective drugs that target HGMs are given as examples to illustrate the concept. Different from most of the single-target drugs that interrupt disease signal pathway(s), neg-entropy drugs treat chronic diseases through converting disorderliness to orderliness in the body of patients. We hope it to be helpful in future drug discovery for chronic diseases.
Attenuated Salmonella secreting interleukin-21 activates T-cells and induces anti-tumor effects

Acta Pharmaceutica Sinica B. 2026, 16(1): 239-251.

The tumor microenvironment is characterized by an immunosuppressive state. Although PD-1/PD-L1 blockade therapy activates the immune system against tumors, it has limited long-term efficacy, prompting the development of combination therapies with targeted treatments to improve cancer treatment outcomes. Recent advancements have revitalized interest in using attenuated Salmonella strains as cancer therapeutics that target tumors, induce immune responses, and promote tumor cell death, although complete tumor suppression remains challenging. We aimed to induce antitumor effects by activating the suppressed immune system within the tumor microenvironment using Salmonella-mediated secretion of interleukin-21 (IL-21). We used the tumor-targeting ability of Salmonella and its flagellar type-3 secretion system (FT3SS) to induce the secretion of IL-21 into the tumor microenvironment via the flagellar system and evaluated the local immune response. We also evaluated the efficacy of combining Salmonella-mediated IL-21 delivery and anti-PD-L1 therapy in a mouse model. IL-21 secretion promoted the recruitment of CD4⁺ and CD8⁺ T cells and enhanced the expression of cytotoxicity-related molecules. Tumor-bearing mice treated with the combination therapy with anti-PD-L1 antibodies showed improved survival rates and enhanced tumor growth inhibition. This study demonstrates the tumor-targeting capability and in vivo safety of Salmonella, highlighting its potential as a powerful cancer therapy platform.
Radiation-induced nuclear translocation of NPRL2 hijacks E3 ubiquitin ligases to enhance DNA repair via the AMPK/WDR24 axis, contributing to CRC radioresistance

Acta Pharmaceutica Sinica B. 2026, 16(1): 252-269.

Radiotherapy resistance remains a major clinical challenge in colorectal cancer (CRC) treatment. Our study reveals that the regulation of nuclear E3 ubiquitin ligase maintains K48-ubiquitin levels that correlate with CRC radiotherapy sensitivity. We identify NPRL2 as the central mediator of this process. Following radiation, NPRL2 rapidly translocates to the nucleus, where it directly binds to the catalytic domains of key E3 ubiquitin ligases, including HERC2 and RNF8, and functionally inactivates them. This NPRL2-mediated inhibition of E3 ligase activity prevents the degradation of critical DNA repair proteins. Importantly, clinical analyses demonstrate that nuclear NPRL2 plays a role in sustaining radioresistance. Mechanistic investigations reveal that radiation-induced AMPK activation initiates this process by phosphorylating WDR24, which promotes NPRL2 dissociation from the GATOR1 complex and facilitates its nuclear translocation. Therapeutic targeting through AMPK inhibition effectively blocks NPRL2 nuclear accumulation, leading to impaired DNA damage repair and significant radiosensitization of CRC cells in both in vitro and in vivo models. These findings not only elucidate the AMPK/WDR24/NPRL2 signaling axis as a fundamental regulator of DNA repair machinery in CRC, but also provide compelling evidence for its potential as a novel therapeutic target to overcome radioresistance and improve radiotherapy efficacy in CRC patients.
Palmitoylation of Tfr1 enhances platelet ferroptosis and liver injury in heat stroke

Qiyuan An, Riqing Wei, Zhicheng Huang, Youyong Tang, Minghao Wang, Sixiao He, Kaihua Huang, Zhifeng Liu, Meimei Zhang, Ru Li, Junhao Huang, Keying Zhang, Jingjing Ji, Liwei Xie, Qiang Ma

Acta Pharmaceutica Sinica B. 2026, 16(1): 270-286.

Heat stroke (HS) is a severe medical emergency characterized by coagulation and high mortality due to organ injury. This study identifies a novel mechanism in which platelet ferroptosis, driven by transferrin receptor 1 (Tfr1) palmitoylation, significantly contributes to liver injury in HS. Our findings reveal a strong inverse correlation between platelet count and organ damage, especially liver injury, as well as mortality rates. Using murine models, we demonstrate that inhibiting Tfr1-mediated ferroptosis in platelets mitigates thrombocytopenia and decreases Interleukin-1β (IL-1β) secretion, thereby improving liver function and survival outcomes. This research highlights Tfr1 palmitoylation as a critical factor in iron transport within platelets, with the palmitoylation inhibitor 2-bromopalmitate (2BP) effectively reducing total iron, Fe²⁺, lipid ROS, 4-hydroxynonenal (4-HNE), and cell cytotoxicity under heat stress. These results suggest that targeting Tfr1 palmitoylation-dependent ferroptosis in platelets offers a novel therapeutic strategy for treating HS-induced thrombocytopenia and liver injury.
DHL-11, a novel prieurianin-type limonoid isolated from Munronia henryi, targeting IMPDH2 to inhibit triple-negative breast cancer

Acta Pharmaceutica Sinica B. 2026, 16(1): 287-304.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by the poorest prognosis, and poses a significant threat to women's health. In this study, we identified two novel prieurianin-type limonoids extracted from Munronia henryi, one of which, named DHL-11, exhibited antitumor activity against TNBC cells. DHL-11 suppressed cell proliferation and migration, induced G2/M cell cycle arrest and apoptosis, and effectively increased the accumulation of reactive oxygen species (ROS) and cellular DNA damage in TNBC cells. Mechanistically, we found that DHL-11 binds to the non-catalytic pocket of IMPDH2 and disrupts the interaction between IMPDH2 and FANCI, leading to the degradation of the IMPDH2 protein. The decrease of IMPDH2 protein reduced guanine synthesis, increased ROS levels, and induced DNA damage. DHL-11 significantly inhibited the growth of breast cancer patient-derived organoids with high IMPDH2 expression. Furthermore, DHL-11 inhibited the growth and metastasis of TNBC xenografts in vivo with favorable biosafety profiles. Our findings highlight the potential of DHL-11 as a novel IMPDH2 degrader for the treatment of IMPDH2-positive TNBC.
Engineered cyclic peptide targeting ITGA5 disrupts tumor-stroma interaction to overcome desmoplasia and resistance in pancreatic ductal adenocarcinoma

Deby Fajar Mardhian, Kunal P. Pednekar, Ahmed G. Hemdan, Praneeth Reddy Kuninty, Saadia A. Karim, Sabine de Winter, Josbert M. Metselaar, Jennifer P. Morton, Jai Prakash

Acta Pharmaceutica Sinica B. 2026, 16(1): 305-321.

The tumor-stroma interaction contributes to the aggressive and resistance nature of pancreatic ductal adenocarcinoma (PDAC), leading to treatment failure. Cancer-associated fibroblasts (CAFs), a key cell type in the stroma, produce abundant extracellular matrix (ECM) and exhibit crosstalk with cancer cells inducing chemoresistance. In this study, we designed a cyclic peptide (cyAV3.3) targeting integrin α5 (ITGA5) to disrupt CAF-induced desmoplasia and crosstalk with cancer cells. In vitro, cyAV3.3 inhibited the differentiation of pancreatic stellate cells into CAFs and reduced ECM production. In 3D co-cultured human spheroid models, the peptide decreased markers of resistance (ABCG1, BCL2, CXCR4), stemness (WNT1, CD44) and ECM remodeling (COL1A1, MMP2/9, LOX) and enhanced gemcitabine efficacy. In vivo, radiolabeled cyAV3.3 exhibited high tumor accumulation and retention following parenteral injections in a co-injection xenograft tumor model. Intriguingly, combination of cyAV3.3 with gemcitabine resulted in improved therapeutic efficacy of gemcitabine in co-injection xenograft and genetically engineered LSL-KrasG¹²D/⁺ LSL-Trp53R¹⁷²H/⁺ Pdx1-Cre (KPC) PDAC models. These effects were attributed to reduced desmoplasia, vasculature compression and enhanced infiltration of cytotoxic T cells and apoptosis. This study presents a novel cyclic peptide inhibiting ITGA5-mediated tumor-stroma interaction and thereby reduce desmoplasia and resistance, ultimately enhancing chemotherapy efficacy in PDAC.
USP10-mediated deubiquitination and activation of KRAS mutants promotes colorectal cancer via a novel USP10/KRAS positive feedback circuit

Tao Yuan, Weihua Wang, Ruilin Wu, Yue Liu, Junwei Fu, Jiamin Du, Meijia Qian, Jia'er Wang, Yubo Zhang, Wencheng Kong, Ronggui Hu, Tianhua Zhou, Qiaojun He, Bo Yang, Hong Zhu

Acta Pharmaceutica Sinica B. 2026, 16(1): 322-336.

Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation is associated with the poor prognosis of colorectal cancer (CRC) patients, but the therapeutic strategies targeting KRAS are limited, and novel intervention strategies are urgently needed. The dysfunction of deubiquitinases (DUBs) is widely involved in the progression of malignancy, and DUBs are considered ideal anti-tumor targets due to their well-defined structures and catalytic sites. In our study, through DUB inhibitors screening and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, we identified that ubiquitin-specific protease 10 (USP10) functions as a potent DUB regulating KRAS mutants' activity. Mechanistically, USP10 directly binds to and promotes KRAS variants' activity across different mutants by removing the latter’s non-proteolytic ubiquitination chains mainly containing K6, K11, K27 and K29-linkage; while the activated KRAS mutants reciprocally upregulate USP10 levels by phosphorylating the latter at Thr42/Ser337, therefore forming a positive feedback circuit and synergistically promoting KRAS-mutant CRC growth. Moreover, we found that USP10 is elevated in KRAS-mutant CRC tissues and depletion of USP10 preferentially impeded KRAS-mutant CRC growth in vitro/in vivo. Our findings not only uncover the critical roles of the USP10/KRAS positive feedback circuit in promoting KRAS-mutant CRC growth, but also offer novel therapeutic strategies for CRC patients harboring KRAS variants across different mutants by targeting USP10.
Gambogenic acid ameliorates inflammation by inhibiting HK1-mediated Warburg effect and NLRP3 inflammasome activation in sepsis

Acta Pharmaceutica Sinica B. 2026, 16(1): 337-351.

Sepsis is a life-threatening disease caused by the dysregulated host immune response to infection, which eventually leads to multi-organ failure. Current therapeutic strategies rely heavily on antibiotics. However, conventional antimicrobial therapy often leads to antibiotic abuse and resistance. Therefore, it is of utmost importance to develop new agents for treating sepsis. Here, we demonstrated that gambogenic acid (GNA) not only restricted the release of inflammatory cytokines in lipopolysaccharide (LPS)-stimulated macrophages but also attenuated the inflammatory response and organ damage in septic mice. By using the activity-based protein profiling (ABPP) strategy, we identified 30 potential target proteins of GNA. Among these potential targets, we found that GNA directly bound to the Cys684 residue of hexokinase 1 (HK1) and affected its enzyme activity and cellular localization. These findings were confirmed by the cellular thermal shift assay (CETSA), bio-layer interferometry (BLI), and single-site mutation experiments. Functionally, siHK1 alleviated the Warburg effect, suppressed the activation of NLRP3 inflammasome, and eventually suppressed the release of inflammatory cytokines. Taken together, our findings demonstrated that GNA could attenuate inflammation by alleviating HK1-mediated Warburg effect and NLRP3 inflammasome activation in sepsis and could serve as a novel therapeutic agent for sepsis and inflammatory disorders.
Chinese medicine and intermittent fasting integration therapy attenuate diabetic vascular calcification via miR21-5p/Tpm1-mediated osteogenic differentiation of VSMCs

Wenting Wang, Yanfei Liu, Yiwen Li, Qian Xu, Mengmeng Zhu, Jing Cui, Yue Liu

Acta Pharmaceutica Sinica B. 2026, 16(1): 352-370.

Vascular calcification (VC) is a marker of substantial vascular damage in patients with diabetes and has been recognized as a predictor of cardiovascular events and all-cause mortality. To date, no effective therapeutic strategy has been formulated for the management of VC. In this study, we integrated the treatment regimen of the Danlian-Tongmai (DLTM) formula, a traditional Chinese medicine (TCM) with anti-diabetic VC (anti-DVC) effects with intermittent fasting (IF), and established the Chinese medicine and intermittent fasting integration therapy (CMIT). CMIT synergistically enhanced the regulation of calcium-phosphorus homeostasis and vascular repair, and demonstrated significantly greater efficacy than DLTM or IF monotherapy in inhibiting calcium deposition and osteogenic differentiation both in vivo and in vitro. Transcriptomic sequencing revealed that the miR21-5p/Tpm1 axis mediated the anti-calcification effect of CMIT. MiR21-5p promoted the overproliferation, migration, and osteogenic differentiation of vascular smooth muscle cells (VSMC) by negatively regulating Tpm1, while CMIT inhibited such processes. In conclusion, this study demonstrated that CMIT inhibited the osteogenic differentiation of VSMC and restored its contractile phenotype by inhibiting the activation of the miR21-5p/Tpm1 axis, thus exerting a therapeutic effect on DVC. CMIT may be a promising approach for the treatment of DVC.
Structure-guided design of picomolar-level macrocyclic TRPC5 channel inhibitors with antidepressant activity

Acta Pharmaceutica Sinica B. 2026, 16(1): 371-386.

Recent advances in ion channel structural biology have enhanced structure-based drug design, yet lipid-occupied binding pockets—often large and flat—remain a major hurdle for developing selective small molecules. TRPC5, a brain-enriched channel regulating depression and anxiety, is a promising therapeutic target, but current preclinical candidates suffer from moderate off-target effects. To address this, we designed macrocyclic TRPC5 inhibitors using structure-guided macrocyclization, overcoming lipid-binding site challenges. Among these, JDIC-127 exhibited unprecedented potency with IC₅₀ of 374 pmol/L—200-fold more potent than HC-070—and exceptional selectivity. Its specificity arises from interactions with unique structural features near the S5 and S6 helices of TRPC5, minimizing activity against related TRPC channels and other ion channels. This selective inhibition aligns with preclinical evidence supporting JDIC-127's potential in treating neuropsychiatric disorders. The study demonstrates how macrocycles stabilize ligand conformations, enhance affinity, and achieve selectivity in lipid-dominated binding sites. It also highlights the synergy between macrocyclic design, cryo-EM, and computational modeling to address longstanding obstacles in ion channel drug discovery. JDIC-127 serves as a proof-of-concept for the application of macrocyclization in ion channel pharmacology, offering a roadmap for developing innovative therapeutics targeting TRP channels and beyond, with implications for a wide range of diseases.

Previous 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 Next

Submission

Peer Review

Staff Login