Mechanisms of PANoptosis and relevant small-molecule compounds for fighting diseases.

Pyroptosis, apoptosis, and necroptosis are mainly programmed cell death (PCD) pathways for host defense and homeostasis. PANoptosis is a newly distinct inflammatory PCD pathway that is uniquely regulated by multifaceted PANoptosome complexes and highlights significant crosstalk and coordination among pyroptosis (P), apoptosis (A), and/or necroptosis(N). Although some studies have focused on the possible role of PANpoptosis in diseases, the pathogenesis of PANoptosis is complex and underestimated. Furthermore, the progress of PANoptosis and related agonists or inhibitors in disorders has not yet been thoroughly discussed. In this perspective, we provide perspectives on PANoptosome and PANoptosis in the context of diverse pathological conditions and human diseases. The treatment targeting on PANoptosis is also summarized. In conclusion, PANoptosis is involved in plenty of disorders including but not limited to microbial infections, cancers, acute lung injury/acute respiratory distress syndrome (ALI/ARDS), ischemia-reperfusion, and organic failure. PANoptosis seems to be a double-edged sword in diverse conditions, as PANoptosis induces a negative impact on treatment and prognosis in disorders like COVID-19 and ALI/ARDS, while PANoptosis provides host protection from HSV1 or Francisella novicida infection, and kills cancer cells and suppresses tumor growth in colorectal cancer, adrenocortical carcinoma, and other cancers. Compounds and endogenous molecules focused on PANoptosis are promising therapeutic strategies, which can act on PANoptosomes-associated members to regulate PANoptosis. More researches on PANoptosis are needed to better understand the pathology of human conditions and develop better treatment.

Analysis of the association between Janus kinase inhibitors and malignant skin tumors using the Food and Drug Administration Adverse Event Reporting System.

BACKGROUND: Malignant skin tumors are adverse events of concern regarding Janus kinase (JAK) inhibitors. AIM: This study aimed to evaluate the association between JAK inhibitors and adverse events of malignant skin tumors, and to characterize the main features. METHOD: Data (2012-2021) were collected using the US Food and Drug Administration Adverse Event Reporting System (FAERS). Adverse event cases of JAK inhibitors as the primary suspected drug were extracted for further analysis. Disproportionality analysis evaluated the association between JAK inhibitors and malignant skin tumor events by estimating the reporting odds ratio (ROR) and the information component (IC) with 95% confidence intervals (95% CI). RESULTS: A total of 142,673 cases with JAK inhibitors as a primary suspected drug were collected, including 1400 malignant skin tumor events. Ruxolitinib, upadacitinib, tofacitinib, and baricitinib were included in the disproportionality analysis. Three JAK inhibitors were associated with malignant skin tumor events, namely ruxolitinib (ROR 5.40, 95% CI 5.03-5.81; IC 2.39, 95% CI 2.14-2.62), upadacitinib (ROR 4.79, 95% CI 4.03-5.71; IC 2.24, 95% CI 1.62-2.77), and tofacitinib (ROR 1.67, 95% CI 1.53-1.83; IC 0.73, 95% CI 0.43-1.02). The median time to onset time was 378.5 days. CONCLUSION: We found association between malignant skin tumors and ruxolitinib, upadacitinib, and tofacitinib. More attention should be paid to these events when prescribing JAK inhibitors in clinical practice.

Biomimetic Cell-Derived Nanoparticles: Emerging Platforms for Cancer Immunotherapy.

Cancer immunotherapy can significantly prevent tumor growth and metastasis by activating the autoimmune system without destroying normal cells. Although cancer immunotherapy has made some achievements in clinical cancer treatment, it is still restricted by systemic immunotoxicity, immune cell dysfunction, cancer heterogeneity, and the immunosuppressive tumor microenvironment (ITME). Biomimetic cell-derived nanoparticles are attracting considerable interest due to their better biocompatibility and lower immunogenicity. Moreover, biomimetic cell-derived nanoparticles can achieve different preferred biological effects due to their inherent abundant source cell-relevant functions. This review summarizes the latest developments in biomimetic cell-derived nanoparticles for cancer immunotherapy, discusses the applications of each biomimetic system in cancer immunotherapy, and analyzes the challenges for clinical transformation.

Cost-effectiveness analysis of trastuzumab deruxtecan in patients with HER2-low advanced breast cancer based on DESTINY-Breast04.

Background and purpose: Breast cancer is a rapidly raising healthcare problem worldwide. DESTINY-Breast04 demonstrated that trastuzumab deruxtecan (T-Dxd) had a survival advantage comparing to the physician's choice of chemotherapy for patients with HER2-low metastatic breast cancer. But at the same time, this expensive novel treatment also brought an economic burden. This study assessed the cost-effectiveness of T-Dxd based on results of DESTINY-Breast04 from the perspective of Chinese healthcare system. Materials and methods: A three-state partitioned-survival model [progression-free survival (PFS), progressive disease (PD) and death] based on data from DESTINY-Breast04 and Chinese healthcare system was used to estimate the incremental cost-effectiveness ratio (ICER) of T-Dxd vs. the physician's choice of chemotherapy for HER2-low metastatic breast cancer. Costs, quality-adjusted life-years (QALYs) and the ICER in terms of 2022 US$ per QALY gained were calculated for both hormone receptor-positive cohort and all patients. One-way and probabilistic sensitivity analyses were performed to assess the model robustness. Results: Compared with the physician's choice of chemotherapy, T-Dxd increased costs by $104,168.30, while gaining 0.31 QALYs, resulting in an ICER of $336,026.77 per QALY in all patients. The costs of T-Dxd and the utility of PFS were the crucial factors in determining the ICER. In the hormone receptor-positive cohort, the ICER was lower than that in all patients, with the ICER of $274,905.72 per QALY. The ICER was much higher than the commonly accepted willingness-to-pay threshold ($357,96.83 per QALY). Conclusion: T-Dxd as second- or subsequent-line treatment is not a cost-effective treatment option for HER2-low metastatic breast cancer from the perspective of the Chinese healthcare system.

Targeting glutaminase 1 (GLS1) by small molecules for anticancer therapeutics.

Glutaminase-1 (GLS1) is a critical enzyme involved in several cellular processes, and its overexpression has been linked to the development and progression of cancer. Based on existing research, GLS1 plays a crucial role in the metabolic activities of cancer cells, promoting rapid proliferation, cell survival, and immune evasion. Therefore, targeting GLS1 has been proposed as a promising cancer therapy strategy, with several GLS1 inhibitors currently under development. To date, several GLS1 inhibitors have been identified, which can be broadly classified into two types: active site and allosteric inhibitors. Despite their pre-clinical effectiveness, only a few number of these inhibitors have advanced to initial clinical trials. Hence, the present medical research emphasizes the need for developing small molecule inhibitors of GLS1 possessing significantly high potency and selectivity. In this manuscript, we aim to summarize the regulatory role of GLS1 in physiological and pathophysiological processes. We also provide a comprehensive overview of the development of GLS1 inhibitors, focusing on multiple aspects such as target selectivity, in vitro and in vivo potency and structure-activity relationships.

Recent Advances on Small-Molecule Bromodomain-Containing Histone Acetyltransferase Inhibitors.

In recent years, substantial research has been conducted on molecular mechanisms and inhibitors targeting bromodomains (BRDs) and extra-terminal (BET) family proteins. On this basis, non-BET BRD is gradually becoming a research hot spot. BRDs are abundant in histone acetyltransferase (HAT)-associated activating transcription factors, and BRD-containing HATs have been linked to cancer, inflammation, and viral replication. Therefore, the development of BRD-containing HATs as chemical probes is useful for understanding the specific biological roles of BRDs in diseases and drug discovery. Several types of BRD-containing HATs, including CBP/P300, PCAF/GCN5, and TAF1, are discussed in this context in terms of their structures, functions, and small-molecule inhibitors. Additionally, progress in BRD inhibitors/chemical probes and proteolysis targeting chimeras in terms of drug design, biological activity, and disease application are summarized. These findings provide insights into the development of BRD inhibitors as potential drug candidates for various diseases.

Analysis of adverse event of interstitial lung disease in men with prostate cancer receiving hormone therapy using the Food and Drug Administration Adverse Event Reporting System.

AIMS: To investigate interstitial lung disease (ILD) in men with prostate cancer receiving hormone therapy. METHODS: We gathered cases diagnosed with prostate cancer based on the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database from 2004 to 2020. We divided the included cases into 3 groups based on the primary suspected drugs: a hormone therapy group, a positive control group (taxanes), and a negative control group. We employed reporting odds ratio, a disproportionality method, to detect the association between ILD events and target drugs. RESULTS: We finally included a total of 85 403 cases, 69 894 cases (628 ILD event cases) in the hormone therapy group, 2302 cases (158 ILD event cases) in the positive control group and 13 207 cases (72 ILD event cases) in the negative control group. There were 394 ILD event cases (62.74%) in the hormone therapy group in Japan; 78.68% of the ILD events occurred within the first year after hormone treatment. Disproportionality analysis indicated that ILD events were significantly associated with nilutamide, flutamide, bicalutamide, goserelin, degarelix and apalutamide; the reporting odds ratios (95% confidence interval) were 32.14 (11.03-93.63), 9.93 (3.62-27.21), 8.19 (6.01-11.16), 3.74 (2.61-5.37), 2.41 (1.55-3.75) and 1.94 (1.01-3.75), respectively. CONCLUSION: Based on this FAERS pharmacovigilance analysis, the association between ILD events and hormone therapy drugs, including bicalutamide, flutamide, nilutamide, goserelin, degarelix and apalutamide, should not be ignored, especially in the Japanese population. Lung function of prostate cancer patients should be monitored when receiving the hormone therapy drugs mentioned above, especially for the first year post medication.

Impact of the expert consensus on polypharmacy and potentially inappropriate medication use in elderly lung cancer outpatients with multimorbidity: An interrupted time series analysis, 2016-2021.

Objectives: Elderly lung cancer patients often have chronic diseases other than lung cancer. Therefore, this kind of population is often accompanied by polypharmacy. This situation and the resulting potentially inappropriate medication (PIM) use are an increasing global concern. In this context, the Chinese Association of Geriatric Research issued an expert consensus on the safety management of polypharmacy. However, the long- and short-term effects of the expert consensus on polypharmacy and PIM use are not clear. Methods: The study was conducted in Chengdu, a city in southwestern China, consisting of prescriptions for elderly lung cancer outpatients with multimorbidity (cancer with other diseases) from January 2016 to December 2021. The 2019 Beers criteria were used to evaluate PIM use, and interrupted time series analysis was used to evaluate the longitudinal effectiveness of expert consensus by measuring the prevalence of polypharmacy and PIM use. We used R software version 4.2.0 for data analysis. Results: A total of 7,238 elderly lung cancer outpatient prescriptions were included in the study. After the publication of the expert consensus, the level (ß = -10.273, P < 0.001) of the prevalence of polypharmacy decreased, but the trend (ß = 0.158, p = 0.855) of polypharmacy increased. The prevalence of PIM use decreased abruptly (ß = -22.828, p < 0.001) after the intervention, but the long-term trend was still upward (ß = 0.907, p = 0.916). Conclusion: The long-term effects of the publication of the expert consensus on the prevalence of polypharmacy and PIM use in hospitals in Chengdu were not optimal. Future research on interventions rationing polypharmacy and PIM use is needed.

Nanomedicines for Overcoming Cancer Drug Resistance.

Clinically, cancer drug resistance to chemotherapy, targeted therapy or immunotherapy remains the main impediment towards curative cancer therapy, which leads directly to treatment failure along with extended hospital stays, increased medical costs and high mortality. Therefore, increasing attention has been paid to nanotechnology-based delivery systems for overcoming drug resistance in cancer. In this respect, novel tumor-targeting nanomedicines offer fairly effective therapeutic strategies for surmounting the various limitations of chemotherapy, targeted therapy and immunotherapy, enabling more precise cancer treatment, more convenient monitoring of treatment agents, as well as surmounting cancer drug resistance, including multidrug resistance (MDR). Nanotechnology-based delivery systems, including liposomes, polymer micelles, nanoparticles (NPs), and DNA nanostructures, enable a large number of properly designed therapeutic nanomedicines. In this paper, we review the different mechanisms of cancer drug resistance to chemotherapy, targeted therapy and immunotherapy, and discuss the latest developments in nanomedicines for overcoming cancer drug resistance.

Recent progress on vascular endothelial growth factor receptor inhibitors with dual targeting capabilities for tumor therapy.

Vascular endothelial growth factor receptors (VEGFRs) are a family of receptor protein tyrosine kinases that play an important role in the regulation of tumor-induced angiogenesis. Currently, VEGFR inhibitors have been widely used in the treatment of various tumors. However, current VEGFR inhibitors are limited to a certain extent due to limited clinical efficacy and potential toxicity, which hinder their clinical application. Thus, the development of new strategies to improve the clinical outcomes and minimize the toxic effects of VEGFR inhibitors is required. Given the synergistic effect of VEGFR and other therapies in tumor development and progression, VEGFR dual-target inhibitors are becoming an attractive approach due to their favorable pharmacodynamics, low toxicity, and anti-resistant effects. This perspective provides an overview of the development of VEGFR dual-target inhibitors from multiple aspects, including rational target combinations, drug discovery strategies, structure-activity relationships and future directions.

ProNGF/NGF Modulates Autophagy and Apoptosis through PI3K/Akt/mTOR and ERK Signaling Pathways following Cerebral Ischemia-Reperfusion in Rats.

NGF is involved in the process of autophagy; however, the underlying mechanisms of proNGF/NGF on autophagy in cerebral ischemia-reperfusion (CIR) remain unclear. This study explored the potential pathway of proNGF/NGF in mediating autophagy and apoptosis and thereby contributed to poststroke neurological rehabilitation. In this study, PC12 cell lines and male SD rats were used to simulate CIR; it was found that within 24 h reperfusion, proNGF was the predominant form of Ngf while after 24 h NGF was produced by proNGF transformation. The mature NGF was found to protect neurons against autophagic and apoptotic damage caused by CIR, but proNGF can cause both autophagic and apoptotic neuronal damage. The protective effect of NGF is associated with the activation of the PI3K/Akt/mTOR and ERK pathway and, as well as the change of autophagy-related proteins. On the other hand, proNGF promoted the ERK pathway increasing autophagy and affected the apoptosis-related proteins in vivo and in vitro. These results were also verified in male SD rats with CIR that neurological deficit caused by CIR can be rescued by recombinant and wild-type NGF, and vice-versa by proNGF.

Targeting Bromodomain-Selective Inhibitors of BET Proteins in Drug Discovery and Development.

Blocking the interactions between bromodomain and extraterminal (BET) proteins and acetylated lysines of histones by small molecules has important implications for the treatment of cancers and other diseases. Many pan-BET inhibitors have shown satisfactory results in clinical trials, but their potential for poor tolerability and toxicity persist. However, recently reported studies illustrate that some BET bromodomain (BET-BD1 or BET-BD2)-selective inhibitors have advantage over pan-inhibitors, including reduced toxicity concerns. Furthermore, some selective BET inhibitors have similar or even better therapeutic efficacy in inflammatory diseases or cancers. Therefore, the development of selective BET inhibitors has become a hot spot for medicinal chemists. Here, we summarize the known selective BET-BD1 and BET-BD2 inhibitors and review the methods for enhancing the selectivity and potency of these inhibitors based on their different modes of interactions with BET-BD1 or BET-BD2. Finally, we discuss prospective strategies that selectively target the bromodomains of BET proteins.

Increased expression of PSME2 is associated with clear cell renal cell carcinoma invasion by regulating BNIP3­mediated autophagy.

Previous studies have showed that proteasome activator complex subunit 2 (PSME2) may play a role in some types of cancer. However, the involvement of PSME2 in clear cell renal cell carcinoma (ccRCC) remains unknown. The aim of the present study was to assess the poorly understood function of PSME2 expression in renal carcinoma. Using bioinformatics analysis, PSME2 mRNA expression profiles were investigated, along with its potential prognostic value and its functional enrichment. Signaling pathways and putative hub genes associated with PSME2 in ccRCC were identified. Based on the bioinformatics analysis results, immunohistochemistry of human ccRCC samples and renal carcinoma cell lines (CAKI­1 and 786­O) transfected with short interfering RNA targeting PSME2 were analyzed using western blot analysis, reverse transcription­quantitative PCR, immunofluorescence, and Cell Counting Kit­8, Transwell and transmission electron microscope assays. The results showed that when PSME2 expression was knocked down, the invasive abilities of the tumor cell lines were reduced, while autophagy was enhanced. The present study demonstrated that PSME2 was associated with the invasion ability of ccRCC cell lines by inhibiting BNIP3­mediated autophagy. In summary, PSME2 could be used as a prognostic factor and a promising therapeutic target in ccRCC.

Design, synthesis, and biological evaluation of nitroisoxazole-containing spiro[pyrrolidin-oxindole] derivatives as novel glutathione peroxidase 4/mouse double minute 2 dual inhibitors that inhibit breast adenocarcinoma cell proliferation.

A series of highly active CF3-containing 3'-(nitroisoxazole)spiro[pyrrolidin-3,2'-oxindoles] were synthesized and found to be novel glutathione peroxidase 4 (GPX4)/mouse double minute 2 (MDM2) dual inhibitors. Bioactive spirooxindole and isoxazole skeletons were combined, and the resulting compounds exhibited strong activities against both targets. In particular, compound 3d displayed excellent activity in the suppression of MDM2-mediated degradation of p53, as well as levels of GPX4, in MCF-7 breast cancer cells. Moreover, 3d also exhibited inhibitory effects on MDM2 and GPX4 in MCF-7 xenograft model to trigger ferroptotic and apoptotic cell death in in vivo experiments, which was consistent with the results of in vitro experiments.

Discovery of Thieno[2,3-d]pyrimidine-Based Hydroxamic Acid Derivatives as Bromodomain-Containing Protein 4/Histone Deacetylase Dual Inhibitors Induce Autophagic Cell Death in Colorectal Carcinoma Cells.

Bromodomain-containing protein 4 (BRD4) and histone deacetylases (HDAC) are both attractive epigenetic targets in cancer and other chronic diseases. Based on the integrated fragment-based drug design, synthesis, and in vitro and in vivo evaluations, a series of novel thieno[2,3-d]pyrimidine-based hydroxamic acid derivatives are discovered as selective BRD4-HDAC dual inhibitors. Compound 17c is the most potent inhibitor for BRD4 and HDAC with IC50 values at nanomolar levels, as well as the expression level of c-Myc, and increases the acetylation of histone H3. Moreover, 17c presents inhibitory effects on the proliferation of colorectal carcinoma (CRC) cells via inducing autophagic cell death. It also has a good pharmacokinetic profile in rats and oral bioavailability of 40.5%. In the HCT-116 xenograft in vivo models, 17c displays potent inhibitory efficiency on tumor growth by inducing autophagic cell death and suppressing IL6-JAK-STAT signaling pathways. Our results suggest that the BRD4-HDAC dual inhibition might be an attractive therapeutic strategy for CRC.

Discovery of novel akt1 inhibitor induces autophagy associated death in hepatocellular carcinoma cells.

In this study, a series of thieno [2,3-d]pyrimidine derivatives were designed, synthesized and evaluated as novel AKT1 inhibitors. In vitro antitumor assay results showed that compounds 9d-g and 9i potently suppressed the enzymatic activities of AKT1 and potently inhibited the proliferation of HepG2, Hep3B, Huh-7 and SMMC-7721 cancer cell lines. Among these derivatives, the compound 9f demonstrated the best inhibitory activities on AKT1 (IC50 = 0.034 µM) and Huh-7 cell (IC50 = 0.076 µM). A panel of biological assays showed that compound 9f suppressed the cellular proliferation of Huh-7 through Akt/mTOR signaling pathway mediated autophagy mechanism. Furthermore, the antitumor capacity of 9f was validated in the subcutaneous Huh-7 xenograft models. Together, our results demonstrate that a novel small-molecule Akt1 inhibitor induces autophagy associated death in hepatocellular carcinoma, which may afford a potential drug candidate for targeted cancer therapy.

Shikonin induces colorectal carcinoma cells apoptosis and autophagy by targeting galectin-1/JNK signaling axis.

Colorectal carcinoma (CRC) is the third most common malignant tumor pathology worldwide. Despite progress in surgical procedures and therapy options, CRC is still a considerable cause of cancer-related mortality. In this study, we tested the antitumor effects of shikonin in CRC and tried to identify its potential mechanism. The potential target, molecular mechanism as well as in vitro and in vivo antitumor effects of shikonin in CRC cells were determined by an integrative protocol including quantitative proteomics, RT-PCR, western blotting, RNA interference and overexpression, apoptosis and autophagy assays, etc. Galectin-1 was a potential target of shikonin from the iTRAQ-based proteomic analysis in shikonin-treated SW620 cell. The overexpression and RNA silencing of galectin-1 in two CRC cells suggested that the shikonin sensitivity was correlation to galectin-1 levels. The ROS accumulation induced by shikonin was important to the formation of galectin-1 dimers. Dimer galectin-1 was found to be associated with the activation of JNK and downstream apoptosis or autophagy. Moreover, through functional in vitro studies, we showed that differences in galectin-1 level affected tumor cell proliferation, migration, and invasion. In summary, shikonin induced CRC cells apoptosis and autophagy by targeting galectin-1 and JNK signaling pathway both in vitro and in vivo, which suggested a potential novel therapy target for CRC.

Modified Fe3O4 Magnetic Nanoparticle Delivery of CpG Inhibits Tumor Growth and Spontaneous Pulmonary Metastases to Enhance Immunotherapy.

As a novel toll-like receptor 9 (TLR9) agonist, synthetic unmethylated cytosine-phosphate-guanine (CpG) oligodeoxynucleotides can stimulate a Th1 immune response and potentially be used as therapeutic agents or vaccine adjuvants for the treatment of cancer. However, some drawbacks of CpG limit their applications, such as rapid elimination by nuclease-mediated degradation and poor cellular uptake. Therefore, repeat high-dose drug administration is required for treatment. In this work, a CpG delivery system based on 3-aminopropyltriethoxysilane (APTES)-modified Fe3O4 nanoparticles (FeNPs) was designed and studied for the first time to achieve better bioactivity of CpG. In our results, we designed FeNP-delivered CpG particles (FeNP/CpG) with a small average size of approximately 50 nm by loading CpG into FeNPs. The FeNP/CpG particle delivery system, with enhanced cell uptake of CpG in bone marrow-derived dendritic cells (BMDCs) in vitro and through intratumoral injection, showed significant antitumor ability by stimulating better humoral and cellular immune responses in C26 colon cancer and 4T1 breast cancer xenograft models in vivo over those of free CpG. Moreover, mice treated by FeNP/CpG particles had delayed tumor growth with an inhibitory rate as high as 94.4%. In addition, approximately 50% of the tumors in the C26 model appeared to regress completely. Similarly, there were lower pulmonary metastases and a 69% tumor inhibitory rate in the 4T1 breast cancer tumor model than those in the untreated controls. In addition to their effectiveness, the easy preparation, safety, and high stability of FeNP/CpG particles also make them an attractive antitumor immunotherapy.

Narciclasine induces autophagy-dependent apoptosis in triple-negative breast cancer cells by regulating the AMPK-ULK1 axis.

OBJECTIVES: Autophagy and apoptosis are major types of eukaryotic programmed cell death, and regulating these processes holds promise for treating cancers. In this study, we explored the regulation mechanisms of narciclasine to autophagy and apoptosis processes in triple-negative breast cancer. MATERIALS AND METHODS: Effects of narciclasine on proliferation, apoptosis, and autophagy of HCC-1937 and MDA-MB-231 triple-negative breast cancer (TNBC) cells were assessed using transmission electronic microscopy, flow cytometry following staining with Annexin V-FITC and propidium iodide, RNA sequencing, real-time PCR, and Western blotting. The ability of narciclasine to inhibit growth of human HCC1937 TNBC xenografts in mice was assessed, and potential mechanisms of inhibition were explored using immunohistochemistry. RESULTS: Narciclasine inhibited TNBC cell proliferation and induced autophagy-dependent apoptosis in a dose-dependent manner. These apoptotic effects could be reversed using autophagy inhibitors, including an AMPK inhibitor and ULK1 siRNA. Consistent with these in vitro results, narciclasine significantly inhibited TNBC tumour growth in mice by upregulating autophagy-dependent apoptosis. CONCLUSIONS: Our findings suggest that narciclasine regulates the AMPK-ULK1 signalling axis to promote autophagy-dependent apoptosis, demonstrating therapeutic potential against TNBC.

Lipid-modified cell-penetrating peptide-based self-assembly micelles for co-delivery of narciclasine and siULK1 in hepatocellular carcinoma therapy.

Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer, and one therapeutic approach is to target both the AMPK and autophagy pathways in order to synergistically promote programmed cell death. Here, a series of amphiphilic, lipid-modified cell-penetrating peptides were synthesized and allowed to self-assemble into micelles loaded with the AMPK activator narciclasine (Narc) and short interfering RNA targeting the unc-51-like kinase 1 (siULK1). The size of these micelles, their efficiency of transfection into cells, and their ability to release drug or siRNA cargo in vitro were pH-sensitive, such that drug release was facilitated in the acidic microenvironment of the tumor. Transfecting the micelles into HCC cells significantly inhibited protective autophagy within tumor cells, and delivering the micelles into mice carrying HCC xenografts induced apoptosis, slowed tumor growth, and inhibited autophagy. Our results indicate that co-delivering Narc and siULK1 in biocompatible micelles can safely inhibit tumor growth and protective autophagy, justifying further studies into this promising therapeutic approach against HCC. STATEMENT OF SIGNIFICANCE: We have focused on the targeted therapy of HCC via synergistically inhibiting the autophagy and inducing apoptosis. The lipid-modified cell-penetrating peptide can not only aggregate into micelles to load natural product narciclasine and ULK1 siRNA simultaneously, but also facilitate uptake and endosome escape with a pH-sensitive manner in HepG2 cells. HepG2 cell treated with siULK1-M-Narc has increased apoptotic levels and declined autophagy via the targeted regulation of AMPK-ULK1 signaling axis. The in vivo studies have confirmed that siULK1-M-Narc efficiently reduce the growth of tumor on HCC xenograft models with good safety. Thus, we suppose the lipid-modified cell-penetrating peptide has good application prospects in the targeted combinational therapy of HCC.