Myosin IXb (Myo9b) is a single-headed motor protein in the myosin superfamily. It contains a unique Rho guanosine triphosphatase-activating protein domain, which enables it to regulate cytoskeletal dynamics and cell migration. Most studies on Myo9b are focused on epithelial repair, intestinal barrier function, and immune cell motility; however, its roles in immune regulation, inflammatory responses, tumorigenesis, and various autoimmune diseases have garnered notable attention in recent years. This study comprehensively reviews the structural characteristics, regulatory mechanisms, and biological functions of Myo9b, along with emphasizing its crucial roles in various pathological conditions and its potential as a therapeutic target.

Purpose:Radiotherapy constitutes a cornerstone in the management of hepatocellular carcinoma (HCC), but its efficacy is limited by radioresistance. Sphingolipids, a class of bioactive lipids, have been implicated in the metabolic reprogramming associated with treatment resistance. However, the potential of circulating sphingolipids as non-invasive biomarkers to predict radiosensitivity in HCC patients remains unexplored. Patients and Methods:This prospective study enrolled 61 HCC patients scheduled for radiotherapy (NCT06864221). Pre-treatment plasma samples were analyzed via LC-MS/MS to quantify 13 sphingolipid species. The primary endpoint was objective response rate (ORR) per mRECIST at 12 weeks. Predictive models were developed using multivariate logistic regression with forward selection and LASSO, evaluated by AUC with bootstrap validation, calibration, and decision curve analysis. Longitudinal analysis was performed in a sub-cohort (n=25) with paired pre- and post-radiotherapy plasma samples. Results:The objective response rate was 54.1%. Univariable analysis identified a distinct sphingolipid signature in responders, characterized by significantly lower S1P and higher levels of CER(d18:1/20:0) and CER(d18:1/24:1). These candidate biomarkers, along with significant clinical variables, were entered into multivariate modeling. The optimal integrated model (Model 1), selected via forward selection, comprised S1P, CER(d18:1/20:0), and the clinical factors ALP and TBIL, and excelled at predicting response (bootstrap-corrected AUC=0.930). A second model based on ceramide/S1P balance (CER(d18:1/26:1)/S1P, Total CER(d18:1)/S1P, AFP) also performed robustly (bootstrap-corrected AUC=0.828). Both models showed clinical utility per decision curve analysis. Longitudinal analysis revealed a coordinated metabolic shift in responders, with reduced S1P and elevated CER(d18:1/26:0), supporting a radiation-induced "sphingolipid rheostat" shift toward apoptosis. Conclusion:This exploratory study provides the first clinical evidence that the baseline plasma sphingolipid profile is a potent, non-invasive predictor of HCC radiosensitivity, validating the "sphingolipid rheostat" theory. Our findings establish a framework for sphingolipid-guided precision radiotherapy and lay the necessary groundwork for future large-scale, multi-center validation trials, which hold significant potential to refine patient stratification and advance the development of novel metabolism-targeted interventions.

Background Heart failure with preserved ejection fraction (HFpEF) is a multifaceted syndrome with high morbidity and mortality. Empagliflozin, an SGLT2 (sodium–glucose cotransporter 2) inhibitor, reduces adverse events in patients with HFpEF regardless of glycemic control. However, the precise cardioprotective mechanisms of SGLT2 inhibitor in HFpEF remain underexplored. Methods and Results A “2‐hit” mouse model of HFpEF was developed via the high‐fat diet combined with Nω‐nitro‐L‐arginine methyl ester. Male C57BL/6N mice were assigned to either a control group (n=10) or an HFpEF group (n=20), with the latter receiving empagliflozin (10 mg/kg per day, n=10) or vehicle (n=10) for 8 weeks. Cardiac function, hypertrophy, and fibrosis were evaluated by physiological, biochemical, and histological measurements. Mechanistic analysis, including RNA sequencing, Western blotting, and immunohistochemistry, was conducted. In vitro, H9c2 cardiomyocytes were exposed to angiotensin II and palmitate, followed by empagliflozin treatment. In vivo, empagliflozin treatment improved body weight, blood pressure, glucose tolerance, and reduced cardiac hypertrophy, fibrosis, and diastolic dysfunction in HFpEF mice. Mechanistic analysis revealed that empagliflozin modulated the AMPK (AMP‐activated protein kinase)/mTORC1 (mammalian target of rapamycin complex 1)/autophagy signaling pathway. Specifically, empagliflozin restored the autophagy markers (Beclin1 and LC3‐II [microtubule‐associated protein 1 light chain 3]) and altered the phosphorylation of AMPK, mTOR, and p70S6K (ribosomal protein S6 kinase beta‐1). Inhibition of AMPK or autophagy nullified the antihypertrophic effect of empagliflozin, underscoring the dependence on the AMPK/mTORC1/autophagy pathway. Conclusions Empagliflozin effectively ameliorates cardiac remodeling and diastolic dysfunction in HFpEF by enhancing autophagy via the AMPK/mTORC1 pathway. These findings elucidate the direct cardioprotective mechanisms of empagliflozin and suggest potential therapeutic molecular targets for HFpEF.

BACKGROUND:Triple-negative breast cancer (TNBC) lacks effective therapeutic targets and exhibits high metastatic potential, resulting in poor prognosis. Both STAT3 signaling and pro-survival autophagy are well-established as critical drivers of TNBC metastasis, yet existing therapeutic approaches primarily focus on single-target inhibition. Pulchinenoside E2 (PSE2), a natural compound isolated from Pulsatilla chinensis, has demonstrated anti-proliferative effects on breast cancer cells. However, its effect on TNBC metastasis and whether it acts concurrently with these two pathways remain unclear. PURPOSE:To identify the key molecular targets of PSE2 and elucidate its unique mechanisms in suppressing TNBC metastasis. METHODS:The anti-migratory and anti-invasive effects of PSE2 on multiple TNBC cell lines were assessed using Transwell assays. Network pharmacology analysis was used to identify overlapping genes and core targets associated with PSE2 and TNBC metastasis. STAT3 was identified as a key target through Western blotting, RNA interference, and Transwell experiments. PSE2-STAT3 interactions were investigated via molecular docking, molecular dynamics simulations, and the cellular thermal shift assay (CETSA). In vitro studies with HS-578T and MDA-MB-231 cells evaluated the effects of PSE2 on STAT3 and JAK2 phosphorylation, STAT3 nuclear and mitochondrial functions, autophagy, and the interplay between STAT3 inhibition and autophagic regulation. In vivo, TNBC metastasis mouse models were used to assess PSE2's effects on hepatic and pulmonary metastases. Pharmacokinetic analysis evaluated the compound's clinical translational potential. RESULTS:PSE2 selectively inhibited invasion and migration in TNBC cells. Network analysis identified 41 overlapping genes and 11 core targets, among which STAT3 emerged as a critical mediator of PSE2's anti-metastatic effects. STAT3 demonstrated the lowest binding free energy to PSE2, with binding confirmed by molecular dynamics simulations and CETSA. PSE2 suppressed p-JAK2 (Tyr1007/1008) and p-STAT3 (Tyr705 and Ser727), impaired STAT3 nuclear transcriptional activity, and inhibited STAT3-dependent mitochondrial oxidative phosphorylation. Additionally, PSE2 blocked autophagic flux by impairing lysosomal proteolytic activity, promoting degradation of mature tissue proteases, and disrupting lysosomal acidity, independent of STAT3. Concurrent inhibition of STAT3 phosphorylation and autophagy synergistically enhanced suppression of TNBC cell migration and invasion. In vivo, PSE2 markedly reduced hepatic and pulmonary metastases and exhibited prolonged retention and slower clearance in mice. CONCLUSIONS:PSE2 functions as a dual inhibitor of STAT3 signaling and autophagy, exerting potent anti-metastatic effects in TNBC. Its mechanism involves suppression of STAT3 phosphorylation and induction of lysosomal dysfunction. These findings highlight PSE2 as a promising candidate for the treatment of TNBC metastasis.

Hepatic ischemia-reperfusion injury (HIRI) is a major complication in liver transplantation, hepatic surgeries, and shock-induced acute liver failure. This injury is characterized by mitochondrial dysfunction, oxidative stress, and calcium overload, with the mitochondrial permeability transition pore (mPTP) playing a pivotal role in mediating hepatocyte death. Cyclophilin D (CypD), a key regulator of mPTP opening, has long been associated with the exacerbation of HIRI. However, recent research has uncovered a protective aspect of CypD, revealing that it can regulate intermittent or “flickering” mPTP openings to control calcium overload, preserve mitochondrial integrity, and mitigate damage during ischemic stress. This review highlights the dual role of CypD in regulating mitochondrial damage through mPTP dynamics and its complex interplay with autophagy, specifically mitophagy, in liver injury. We also explore the emerging pharmacological and genetic approaches targeting PPIF, offering potential avenues for mitigating liver injury in clinical settings. This review integrates recent findings on PPIF’s role in mPTP regulation, inflammation, autophagy, and mitophagy, proposing a nuanced view of its therapeutic potential in managing hepatic ischemia-reperfusion injury.

The major histocompatibility complex class I (MHC class I)-mediated tumor antigen processing and presentation (APP) pathway is essential for the recruitment and activation of cytotoxic CD8+ T lymphocytes (CD8+ CTLs). However, this pathway is frequently dysregulated in many cancers, thus leading to a failure of immunotherapy. Here, we report that activation of the tumor-intrinsic Hippo pathway positively correlates with the expression of MHC class I APP genes and the abundance of CD8+ CTLs in mouse tumors and patients. Blocking the Hippo pathway effector Yes-associated protein/transcriptional enhanced associate domain (YAP/TEAD) potently improves antitumor immunity. Mechanistically, the YAP/TEAD complex cooperates with the nucleosome remodeling and deacetylase complex to repress NLRC5 transcription. The upregulation of NLRC5 by YAP/TEAD depletion or pharmacological inhibition increases the expression of MHC class I APP genes and enhances CD8+ CTL-mediated killing of cancer cells. Collectively, our results suggest a crucial tumor-promoting function of YAP depending on NLRC5 to impair the MHC class I APP pathway and provide a rationale for inhibiting YAP activity in immunotherapy for cancer.

(1) Background: Radiation-induced thrombocytopenia (RIT) often occurs in cancer patients undergoing radiation therapy, which can result in morbidity and even death. However, a notable deficiency exists in the availability of specific drugs designed for the treatment of RIT. (2) Methods: In our pursuit of new drugs for RIT treatment, we employed three deep learning (DL) algorithms: convolutional neural network (CNN), deep neural network (DNN), and a hybrid neural network that combines the computational characteristics of the two. These algorithms construct computational models that can screen compounds for drug activity by utilizing the distinct physicochemical properties of the molecules. The best model underwent testing using a set of 10 drugs endorsed by the US Food and Drug Administration (FDA) specifically for the treatment of thrombocytopenia. (3) Results: The Hybrid CNN+DNN (HCD) model demonstrated the most effective predictive performance on the test dataset, achieving an accuracy of 98.3% and a precision of 97.0%. Both metrics surpassed the performance of the other models, and the model predicted that seven FDA drugs would exhibit activity. Isochlorogenic acid A, identified through screening the Chinese Pharmacopoeia Natural Product Library, was subsequently subjected to experimental verification. The results indicated a substantial enhancement in the differentiation and maturation of megakaryocytes (MKs), along with a notable increase in platelet production. (4) Conclusions: This underscores the potential therapeutic efficacy of isochlorogenic acid A in addressing RIT.

Scorpion venom is a potent natural source for antitumor drug development due to the multiple action modes of anticancer components. Although the sequence of Androcin 18-1 has been identified from the transcriptome profile of the scorpion venom Androctonus bicolor, its bioactivity remains unclear. In this study, we described the antitumor mechanism whereby Androcin 18-1 inhibits the proliferation and induces apoptosis by inducing cell membrane disruption, ROS accumulation, and mitochondrial dysfunction in human U87 glioblastoma cells. Moreover, Androcin 18-1 could suppress cell migration via the mechanisms associated with cytoskeleton disorganization and MMPs/TIMPs expression regulation. The discovery of this work highlights the potential application of Androcin 18-1 in drug development for glioblastoma treatment.

The clinical success of KRASG12C inhibitors (G12Ci) including AMG510 and MRTX849 is limited by the eventual development of acquired resistance. A novel and effective treatment to revert or target this resistance is urgent. To this end, we established G12Ci (AMG510 and MRTX849) resistant KRASG12C mutant cancer cell lines and screened with an FDA-approved drug library. We found the ferroptosis inducers including sorafenib and lapatinib stood out with an obvious growth inhibition in the G12Ci resistant cells. Mechanistically, the G12Ci resistant cells exhibited reactivation of MAPK signaling, which repressed SOX2-mediated expression of cystine transporter SLC7A11 and iron exporter SLC40A1. Consequently, the low intracellular GSH level but high iron content engendered hypersensitivity of these resistant tumors to ferroptosis inducers. Ectopic overexpression of SOX2 or SLC7A11 and SLC40A1 conferred resistance to ferroptosis in the G12Ci resistant cells. Ferroptosis induced by sulfasalazine (SAS) achieved obvious inhibition on the tumor growth of xenografts derived from AMG510-resistant KRASG12C-mutant cells. Collectively, our results suggest a novel therapeutic strategy to treat patients bearing G12Ci resistant cancers with ferroptosis inducers.

Distal metastases result from metastatic microenvironment and tumour epithelial cell interactions, the cellular heterogeneity of primary colorectal cancer (CRC) and liver metastases (LM) was evaluated by integrating single-cell sequencing data, and the collected gene expression data from metastatic epithelial cell subsets was used to construct a prognostic model and to identify intercellular receptor-ligand interactions between epithelial and immune cells in CRC and LM. Multiplex immunofluorescence staining, and in vitro wound healing, cell migration and cell apoptosis assays were performed to further explore the biological relevance of identified potential regulatory molecules. In this study, approximately 17 epithelial cell subtypes were detected, with Epi-11 cells being highly expressed in LM tissues compared with CRC samples. Furthermore, patients with high expression of the metastasis-related genetic profile of Epi-11 had a poorer prognosis. By predicting receptor-ligand interactions, Epi-11 cells were found to interact more with myeloid and T/natural killer cells in LM tissues when compared to primary CRC samples, which was mediated by the PLXNB1/SEMA4D axis. In addition, high SEMA4D expression was correlated with decreased overall survival of patients with CRC, whereas PLXNB1 was not. SEMA4D knockdown prevented the migration and promoted the apoptosis of HCT116 cells in vitro. In summary, Epi-11 cells, an important subset of epithelial cells, may drive the LM of CRC and act by crosstalk with immune cells through the PLXNB1/SEMA4D signalling axis.

Citation: Wang K, Yang C, Tao B, Guo S and Wang H (2024) Editorial: Epigenetic regulation of autophagy in inflammatory diseases. Front. Immunol. 15:1387459. doi: 10.3389/fimmu.2024.1387459

SRY-box transcription factor 9 (SOX9) (OMIM 608160) is a transcription factor. The expression of SOX9 in pan-cancers and the regulation by small molecules in cancer cell lines are unclear. In the current study, we comprehensively analyzed the expression of SOX9 in normal tissues, tumor tissues and their matched healthy tissues in pan-cancers. The study examined the correlation between immunomodulators and immune cell infiltrations in normal and tumor tissues. Cordycepin (CD), an adenosine analog for SOX9 expression regulation, was also conducted on cancer cells. The results found that SOX9 protein is expressed in a variety of organs, including high expression in 13 organs and no expression in only two organs; in 44 tissues, there was high expression in 31 tissues, medium expression in four tissues, low expression in two tissues, and no expression in the other seven tissues. In pan-cancers with 33 cancer types, SOX9 expression was significantly increased in fifteen cancers, including CESC, COAD, ESCA, GBM, KIRP, LGG, LIHC, LUSC, OV, PAAD, READ, STAD, THYM, UCES, and UCS, but significantly decreased in only two cancers (SKCM and TGCT) compared with the matched healthy tissues. It suggests that SOX9 expression is upregulated in the most cancer types (15/33) as a proto-oncogene. The fact that the decrease of SOX9 expression in SKCM and the increase of SOX9 in the cell lines of melanoma inhibit tumorigenicity in both mouse and human ex vivo models demonstrates that SOX9 could also be a tumor suppressor. Further analyzing the prognostic values for SOX9 expression in cancer individuals revealed that OS is long in ACC and short in LGG, CESC, and THYM, suggesting that high SOX9 expression is positively correlated with the worst OS in LGG, CESC, and THYM, which could be used as a prognostic maker. In addition, CD inhibited both protein and mRNA expressions of SOX9 in a dose-dependent manner in 22RV1, PC3, and H1975 cells, indicating CD’s anticancer roles likely via SOX9 inhibition. Moreover, SOX9 might play an important role in tumor genesis and development by participating in immune infiltration. Altogether, SOX9 could be a biomarker for diagnostics and prognostics for pan-cancers and an emerging target for the development of anticancer drugs.

Background: In this study, we integrated single-cell RNA sequencing (scRNA-seq) data to investigate cell heterogeneity and utilized MSigDB and CIBERSORTx to explore the pathways of major cell types and the relationships between different cell subtypes. Subsequently, we explored the correlation of cell subtypes with survival and used Gene Set Enrichment Analysis (GSEA) analyses to assess the pathways associated with the infiltration of specific cell subtypes. Finally, multiplex immunohistochemistry in tissue microarray cohort were performed to validate differences in protein level and their correlation with survival. Results: iCCA presented a unique immune ecosystem, with increased proportions of Epi (epithelial)-SPP1-2, EpiS100P-1, Epi-DN (double negative for SPP1 and S100P expression)-1, Epi-DN-2, Epi-DP (double positive for SPP1 and S100P expression)-1, Plasma B-3, Plasma B-2, B-HSPA1A-1, B-HSPA1A-2 cells, and decreased proportions of B-MS4A1. High level of Epi-DN-2, Epi-SPP1-1, Epi-SPP1-2, B-MS4A1, and low level of Epi-DB-1, Epi-S100P-1, and Epi-S100P-2 was significantly associated with longer overall survival (OS), and high level of B-MS4A1_Low_Epi-DN-2_Low was associated with the shortest OS. Moreover, the results of MsigDB and GSEA suggest that bile acid metabolism is a crucial process in iCCA. Finally, we found that S100P+, SPP1+, SPP1 + S100P+, and MS4A1-SPP1 + S100P+ were highly expressed, whereas MS4A1 was lowly expressed in iCCA, and patients with high level of S100P+, SPP1 + S100P+, and MS4A1-SPP1 + S100P+ exhibited shorter survival. Conclusions: We identified the cell heterogeneity of iCCA, found that iCCA is a unique immune ecosystem with many cell subtypes, and showed that the novel cell subtypes of SPP1 + S100P+ and MS4A1-SPP1 + S100P+ were key subpopulations in iCCA.

Immunotherapy is a type of treatment that uses our own immune system to fight cancer. Studies have shown that traditional Chinese medicine (TCM) has antitumor activity and can enhance host immunity. This article briefly describes the immunomodulatory and escape mechanisms in tumors, as well as highlights and summarizes the antitumor immunomodulatory activities of some representative active ingredients of TCM. Finally, this article puts forward some opinions on the future research and clinical application of TCM, aiming to promote the clinical applications of TCM in tumor immunotherapy and to provide new ideas for the research of tumor immunotherapy using TCM.

Antimicrobial peptide is one important component of the first protective barrier of organisms. They not only have potent antimicrobial activity which can protect the body from the invading pathogens, but also participate in the immune regulation of the body. In this study, a Brevinin-1 peptide named by Brevinin-1GHd was identified from Hoplobatrachus rugulosus , and the similarity of mature peptide sequence among Brevinin-1GHd, Brevinin-1HL and Brevinin-1GHa supported the close species relationship between H. rugulosus , Hylarana latouchii and Hylarana guertheri . Moreover, the secondary structure of Brevinin-1GHd was found to possess α-helical characteristics and high thermal stability. In addition, Brevinin-1GHd could bind to LPS with a Kd value of 6.49 ± 5.40 mM and suppress the release of TNF-α, NO, IL-6 and IL-1β by inactivation of MAPK signaling pathway in RAW 264.7 cells induced by LPS. Furtherly, Brevinin-1GHd had a significant inhibitory effect on acute edema development in the right paw of mice injected by carrageenan. Thus, the significant LPS-neutralizing and anti-inflammatory activities of Brevinin-1GHd were demonstrated in this study, which made it become the first Brevinin-1 family peptide with anti-inflammatory activity reported so far, and the biological activity of Brevinin-1GHd made it promising to be a novel therapeutic drug for infectious inflammation.

Cellular heterogeneity and immune cell molecular phenotypes may be involved in the malignant progression of glioblastoma (GBM). In this study, we aimed to know whether the heterogeneity of tumour-associated macrophages contributes to the recurrence and outcomes of glioblastoma patients. Single-cell RNA sequencing (scRNA-Seq) data were used to assess the heterogeneity of CD45 + immune cells in recurrent GBM and analyse differentially expressed genes (DEGs) in master cells. Then, a prognostic signature based on the identified DEGs was established and validated, the correlation between risk score and tumour microenvironment (TME) was explored. The correlation between immune infiltration and LGMN, an important DEG in GBM tumour-associated macrophages (TAMs) was illuminated, using integrated bioinformatics analyses. Finally, immunohistochemistry and multiplex immunohistochemistry (mIHC) were used to analyse the expression of LGMN in GBM tissues from our hospital. scRNA-Seq analysis showed that the heterogeneity of recurrent GBM mainly comes from TAMs, which can be divided into 8 cell subclusters. Among these subclusters, TAM1 (markers: CXCL10, ADORA3), TAM3 (markers: MRC1, CFP), TAM4 (markers: GPNMB, PLTP), and TAM5 (markers: CCL4, IRAK2) were specifically present in recurrent GBM. After 342 DEGs in TAMs were identified, a prognostic signature was established based on 13 TAM-associated DEGs, and this signature could serve as an excellent prognostic predictor for patients with GBM. LGMN, one of 13 TAM-associated DEGs, was an important gene in lysosome pathway, we found that macrophage infiltration levels were higher after LGMN upregulation. GBM tissues from our hospital were collected for histopathologic validation, then LGMN was co-expressed with CD68, which is associated with the immune regulation of GBM. In conclusion, cell heterogeneity of TAMs is important for recurrent GBM, a prognostic signature based on 13 TAM-related DEGs can predict the survival outcome of GBM patients. An important DEG, LGMN may regulate the immune cell infiltration of GBM.

SET8 is the only lysine methyltransferase that can specifically monomethylate the histone H4K20. SET8-mediated protein modifications are largely involved in the regulation of cell cycle, DNA repair, gene transcription, cell apoptosis, and other vital physiological processes. The aberrant expression of SET8 is closely linked to the proliferation, invasion, metastasis, and prognosis of a variety of cancers. As a consequence, targeting SET8 could be an appealing strategy for cancer therapy. In this article, we introduce the molecular structure of SET8, followed by summarizing its roles in various biological pathways. Crucially, we highlight the potential functions of SET8 in tumors, as well as progress in the development of SET inhibitors for cancer treatment.