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Background Radiation-induced liver fibrosis (RILF) is a common manifestation of radiation-induced liver injury (RILI) and is caused primarily by activated hepatic stellate cells (HSCs). Circular RNAs (circRNAs) play critical roles in various diseases, but little is known about the function and mechanism of circRNAs in RILF. Methods RNA pull-down and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used to screen binding proteins of hsa_circ_0096498 (circ96498). RNA-binding protein immunoprecipitation, RNA pull-down and nuclear and cytoplasmic protein extraction were conducted to confirm the interaction between circ96498 and eukaryotic initiation factor 4A3 (EIF4A3). RNA sequencing was performed to screen target genes regulated by EIF4A3. HSCs with altered circ96498 and cell division cycle 42 (CDC42) expression were used to assess irradiated HSC activation. Circ96498 inhibition and CDC42 blockade were evaluated in RILF mouse models. Results In this study, we identified a radiation-sensitive circ96498, which was highly expressed in the irradiated HSCs of paracancerous tissues from RILI patients. Circ96498 inhibited the proliferation but promoted the apoptosis of irradiated HSCs, suppressed the secretion of proinflammatory cytokines IL-1[beta], IL-6 and TNF-[alpha], and decreased the expression of profibrotic markers ([alpha]-SMA and collagen 1) in irradiated HSCs. Mechanistically, irradiation induced the transport of EIF4A3 into the nucleus, and nuclear EIF4A3 increased the stability of CDC42 mRNA and increased CDC42 expression, thereby promoting HSC activation through the NF-κB and JNK/Smad2 pathways. However, the binding of circ96498 to EIF4A3 impeded the translocation of EIF4A3 into the nucleus, resulting in the inhibition of CDC42 expression and subsequent HSC activation. Furthermore, circ96498 knockdown promoted the development of the early and late stages of RILF in a mouse model, which was mitigated by CDC42 blockade. Conclusions Collectively, our findings elucidate the involvement of the circ96498/EIF4A3/CDC42 axis in inhibiting irradiated HSC activation, which offers a novel approach for RILF prevention and treatment. Graphical Keywords: Circular RNA, EIF4A3, CDC42, Hepatic stellate cell, Radiation-induced liver fibrosis

Background Radiation‐induced hepatic stellate cell (HSC) activation promotes radiation‐induced liver fibrosis (RILF), a complication for hepatocellular carcinoma (HCC) radiotherapy. The demethylase alpha‐ketoglutarate‐dependent dioxygenase alkB homolog 5 (ALKBH5) decreases N6‐methyladenylate methylation (m6A) modification of RNA, while its role in regulating RILF pathogenesis and HCC radiosensitivity remains unknown. Methods Methylated RNA immunoprecipitation sequencing (MeRIP‐seq) and RNA‐sequencing (RNA‐seq) were used to screen target genes regulated by ALKBH5. HSC with altered ALKBH5 expression was used to assess irradiation‐induced HSC activation and the effect of HSC on recruitment and polarisation of monocytes. Key cytokines in medium from irradiated HSC‐educated monocytes were identified by cytokine array detection. The effects of blocking ALKBH5 and key cytokines on RILF and HCC radiosensitivity were also evaluated. Results Radiation‐induced ALKBH5 expression in HSC mediated m6A demethylation of toll‐interleukin 1 receptor domain containing adaptor protein (TIRAP) mRNA and activated its downstream NF‐κB and JNK/Smad2 pathways to promote HSC activation. Additionally, ALKBH5 regulated CCL5 secretion by irradiated HSC to promote monocyte recruitment and M2 macrophage polarisation. Notably, polarised monocytes secreted CCL20 to up‐regulate ALKBH5 expression in HSC, and reduce HCC radiosensitivity by activating ALKBH5/TIRAP axis in HCC cells. ALKBH5 knockdown‐combined CCR6 (CCL20 receptor) inhibitor significantly alleviated RILF and improved HCC radiosensitivity in mice. HCC patients with high ALKBH5 and TIRAP expression were prone to radiation‐induced liver injury and poor tumour response to radiotherapy. Conclusions Collectively, irradiation up‐regulates ALKBH5 in HSC to mediate monocyte recruitment and M2 polarisation and form positive feedback to promote RILF and reduce HCC radiosensitivity. The dual roles of ALKBH5 as a microenvironmental regulator and radiosensitisation target provide new ideas for RILF prevention and radiosensitisation of HCC. ALKBH5‐mediated TIRAP mRNA m6A demethylation promotes irradiated HSC activation ALKBH5 regulates the CCL5‐CCR5 axis to promote monocyte recruitment and M2 polarisation Irradiated HSC educated monocyte promotes HSC activation and reduces HCC radiosensitivity by CCL20 secretion Blocking ALKBH5‐CCR6 axis alleviates radiation‐induced liver fibrosis and improves HCC radiosensitivity

Background Radiation-induced liver fibrosis (RILF) is a common manifestation of radiation-induced liver injury (RILI) and is caused primarily by activated hepatic stellate cells (HSCs). Circular RNAs (circRNAs) play critical roles in various diseases, but little is known about the function and mechanism of circRNAs in RILF. Methods RNA pull-down and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used to screen binding proteins of hsa_circ_0096498 (circ96498). RNA-binding protein immunoprecipitation, RNA pull-down and nuclear and cytoplasmic protein extraction were conducted to confirm the interaction between circ96498 and eukaryotic initiation factor 4A3 (EIF4A3). RNA sequencing was performed to screen target genes regulated by EIF4A3. HSCs with altered circ96498 and cell division cycle 42 (CDC42) expression were used to assess irradiated HSC activation. Circ96498 inhibition and CDC42 blockade were evaluated in RILF mouse models. Results In this study, we identified a radiation-sensitive circ96498, which was highly expressed in the irradiated HSCs of paracancerous tissues from RILI patients. Circ96498 inhibited the proliferation but promoted the apoptosis of irradiated HSCs, suppressed the secretion of proinflammatory cytokines IL-1β, IL-6 and TNF-α, and decreased the expression of profibrotic markers (α-SMA and collagen 1) in irradiated HSCs. Mechanistically, irradiation induced the transport of EIF4A3 into the nucleus, and nuclear EIF4A3 increased the stability of CDC42 mRNA and increased CDC42 expression, thereby promoting HSC activation through the NF-κB and JNK/Smad2 pathways. However, the binding of circ96498 to EIF4A3 impeded the translocation of EIF4A3 into the nucleus, resulting in the inhibition of CDC42 expression and subsequent HSC activation. Furthermore, circ96498 knockdown promoted the development of the early and late stages of RILF in a mouse model, which was mitigated by CDC42 blockade. Conclusions Collectively, our findings elucidate the involvement of the circ96498/EIF4A3/CDC42 axis in inhibiting irradiated HSC activation, which offers a novel approach for RILF prevention and treatment. Graphical Abstract

Selective photodecomposition of highly toxic pollutants is a significant challenge because the free radicals produced by photocatalyst show an indistinguishable attack on all contaminants in wastewater. To realize selective photodegradation, an organic imprinted Ag-PANI/CdS/Fe3O4/Biochar photocatalyst (IM-Ag-PANI/CdS/Fe3O4/BC) was successfully prepared by photoinitiated polymerization method. The formation of heterojunction facilitates the separation of photoexcited carriers and effectively inhibits the photocorrosion of CdS, thereby improving the photocatalytic activity and stability of photocatalysts. Moreover, the imprinted cavities in Ag-PANI layer help to selectively adsorb and degrade 2-mercapto-1-methylimidazole (MMIZ), resulting in a high selectivity coefficient of 2.40 relative to 5-Mercapto-1-methyltetrazole, and the photodegradation efficiency of MMIZ is boosted up to 76% within 1 h. This work provides a new idea to construct stable photocatalysts with high selectivity for the decontamination of target pollutants.

Radiation-induced hepatic stellate cell (HSC) activation promotes radiation-induced liver fibrosis (RILF), a complication for hepatocellular carcinoma (HCC) radiotherapy. The demethylase alpha-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) decreases N6-methyladenylate methylation (m6 A) modification of RNA, while its role in regulating RILF pathogenesis and HCC radiosensitivity remains unknown.BACKGROUNDRadiation-induced hepatic stellate cell (HSC) activation promotes radiation-induced liver fibrosis (RILF), a complication for hepatocellular carcinoma (HCC) radiotherapy. The demethylase alpha-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) decreases N6-methyladenylate methylation (m6 A) modification of RNA, while its role in regulating RILF pathogenesis and HCC radiosensitivity remains unknown.Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-sequencing (RNA-seq) were used to screen target genes regulated by ALKBH5. HSC with altered ALKBH5 expression was used to assess irradiation-induced HSC activation and the effect of HSC on recruitment and polarisation of monocytes. Key cytokines in medium from irradiated HSC-educated monocytes were identified by cytokine array detection. The effects of blocking ALKBH5 and key cytokines on RILF and HCC radiosensitivity were also evaluated.METHODSMethylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-sequencing (RNA-seq) were used to screen target genes regulated by ALKBH5. HSC with altered ALKBH5 expression was used to assess irradiation-induced HSC activation and the effect of HSC on recruitment and polarisation of monocytes. Key cytokines in medium from irradiated HSC-educated monocytes were identified by cytokine array detection. The effects of blocking ALKBH5 and key cytokines on RILF and HCC radiosensitivity were also evaluated.Radiation-induced ALKBH5 expression in HSC mediated m6 A demethylation of toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) mRNA and activated its downstream NF-κB and JNK/Smad2 pathways to promote HSC activation. Additionally, ALKBH5 regulated CCL5 secretion by irradiated HSC to promote monocyte recruitment and M2 macrophage polarisation. Notably, polarised monocytes secreted CCL20 to up-regulate ALKBH5 expression in HSC, and reduce HCC radiosensitivity by activating ALKBH5/TIRAP axis in HCC cells. ALKBH5 knockdown-combined CCR6 (CCL20 receptor) inhibitor significantly alleviated RILF and improved HCC radiosensitivity in mice. HCC patients with high ALKBH5 and TIRAP expression were prone to radiation-induced liver injury and poor tumour response to radiotherapy.RESULTSRadiation-induced ALKBH5 expression in HSC mediated m6 A demethylation of toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) mRNA and activated its downstream NF-κB and JNK/Smad2 pathways to promote HSC activation. Additionally, ALKBH5 regulated CCL5 secretion by irradiated HSC to promote monocyte recruitment and M2 macrophage polarisation. Notably, polarised monocytes secreted CCL20 to up-regulate ALKBH5 expression in HSC, and reduce HCC radiosensitivity by activating ALKBH5/TIRAP axis in HCC cells. ALKBH5 knockdown-combined CCR6 (CCL20 receptor) inhibitor significantly alleviated RILF and improved HCC radiosensitivity in mice. HCC patients with high ALKBH5 and TIRAP expression were prone to radiation-induced liver injury and poor tumour response to radiotherapy.Collectively, irradiation up-regulates ALKBH5 in HSC to mediate monocyte recruitment and M2 polarisation and form positive feedback to promote RILF and reduce HCC radiosensitivity. The dual roles of ALKBH5 as a microenvironmental regulator and radiosensitisation target provide new ideas for RILF prevention and radiosensitisation of HCC.CONCLUSIONSCollectively, irradiation up-regulates ALKBH5 in HSC to mediate monocyte recruitment and M2 polarisation and form positive feedback to promote RILF and reduce HCC radiosensitivity. The dual roles of ALKBH5 as a microenvironmental regulator and radiosensitisation target provide new ideas for RILF prevention and radiosensitisation of HCC.

Radiation-induced hepatic stellate cell (HSC) activation promotes radiation-induced liver fibrosis (RILF), a complication for hepatocellular carcinoma (HCC) radiotherapy. The demethylase alpha-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) decreases N6-methyladenylate methylation (m A) modification of RNA, while its role in regulating RILF pathogenesis and HCC radiosensitivity remains unknown. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-sequencing (RNA-seq) were used to screen target genes regulated by ALKBH5. HSC with altered ALKBH5 expression was used to assess irradiation-induced HSC activation and the effect of HSC on recruitment and polarisation of monocytes. Key cytokines in medium from irradiated HSC-educated monocytes were identified by cytokine array detection. The effects of blocking ALKBH5 and key cytokines on RILF and HCC radiosensitivity were also evaluated. Radiation-induced ALKBH5 expression in HSC mediated m A demethylation of toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) mRNA and activated its downstream NF-κB and JNK/Smad2 pathways to promote HSC activation. Additionally, ALKBH5 regulated CCL5 secretion by irradiated HSC to promote monocyte recruitment and M2 macrophage polarisation. Notably, polarised monocytes secreted CCL20 to up-regulate ALKBH5 expression in HSC, and reduce HCC radiosensitivity by activating ALKBH5/TIRAP axis in HCC cells. ALKBH5 knockdown-combined CCR6 (CCL20 receptor) inhibitor significantly alleviated RILF and improved HCC radiosensitivity in mice. HCC patients with high ALKBH5 and TIRAP expression were prone to radiation-induced liver injury and poor tumour response to radiotherapy. Collectively, irradiation up-regulates ALKBH5 in HSC to mediate monocyte recruitment and M2 polarisation and form positive feedback to promote RILF and reduce HCC radiosensitivity. The dual roles of ALKBH5 as a microenvironmental regulator and radiosensitisation target provide new ideas for RILF prevention and radiosensitisation of HCC.

Background： Mastitis, an infection caused by Gram-positive bacteria, produces udder inflammation and oxidative injury in milk-producing mammals. Toll-like receptor 2（TLR2） is important for host recognition of invading Grampositive microbes. Over-expression of TLR2 in transgenic dairy goats is a useful model for studying various aspects of infection with Gram-positive bacteria, in vivo.Methods： We over-expressed TLR2 in transgenic dairy goats. Pam3CSK4, a component of Gram-positive bacteria,triggered the TLR2 signal pathway by stimulating the monocytes-macrophages from the TLR2-positive transgenic goats, and induced over-expression of activator protein-1（AP-1）, phosphatidylinositol 3-kinase（PI3K） and transcription factor nuclear factor kappa B（NF-κB） and inflammation factors downstream of the signal pathway.Results： Compared with wild-type controls, measurements of various oxidative stress-related molecules showed that TLR2, when over-expressed in transgenic goat monocytes-macrophages, resulted in weak lipid damage, high level expression of anti-oxidative stress proteins, and significantly increased m RNA levels of transcription factor NF-E2-related factor-2（Nrf2） and the downstream gene, heme oxygenase-1（HO-1）. When Pam3CSK4 was used to stimulate ear tissue in vivo the HO-1 protein of the transgenic goats had a relatively high expression level.Conclusions： The results indicate that the oxidative injury in goats over-expressing TLR2 was reduced following Pam3CSK4 stimulation. The underlying mechanism for this reduction was increased expression of the anti-oxidation gene HO-1 by activation of the Nrf2 signal pathway.

Renal cell carcinoma (RCC) is one of the three major malignant tumors of the urinary system and originates from proximal tubular epithelial cells. Clear cell renal cell carcinoma (ccRCC) accounts for approximately 80% of RCC cases and is recognized as a metabolic disease driven by genetic mutations and epigenetic alterations. Through bioinformatic analysis, we found that FK506 binding protein 10 (FKBP10) may play an essential role in hypoxia and glycolysis pathways in ccRCC progression. Functionally, FKBP10 promotes the proliferation and metastasis of ccRCC in vivo and in vitro depending on its peptidyl-prolyl cis-trans isomerase (PPIase) domains. Mechanistically, FKBP10 binds directly to lactate dehydrogenase A (LDHA) through its C-terminal region, the key regulator of glycolysis, and enhances the LDHA-Y10 phosphorylation, which results in a hyperactive Warburg effect and the accumulation of histone lactylation. Moreover, HIFα negatively regulates the expression of FKBP10, and inhibition of FKBP10 enhances the antitumor effect of the HIF2α inhibitor PT2385. Therefore, our study demonstrates that FKBP10 promotes clear cell renal cell carcinoma progression and regulates sensitivity to HIF2α blockade by facilitating LDHA phosphorylation, which may be exploited for anticancer therapy.

Current treatment approaches for Prostate cancer (PCa) often come with debilitating side effects and limited therapeutic outcomes. There is urgent need for an alternative effective and safe treatment for PCa. We developed a nanoplatform to target prostate cancer cells based on graphdiyne (GDY) and a copper-based metal-organic framework (GDY-CuMOF), that carries the chemotherapy drug doxorubicin (DOX) for cancer treatment. Moreover, to provide GDY-CuMOF@DOX with homotypic targeting capability, we coated the PCa cell membrane (DU145 cell membrane, DCM) onto the surface of GDY-CuMOF@DOX, thus obtaining a biomimetic nanoplatform (DCM@GDY-CuMOF@DOX). The nanoplatform was characterized by using transmission electron microscope, atomic force microscope, X-ray diffraction, etc. Drug release behavior, antitumor effects in vivo and in vitro, and biosafety of the nanoplatform were evaluated. We found that GDY-CuMOF exhibited a remarkable capability to load DOX mainly through π-conjugation and pore adsorption, and it responsively released DOX and generated Cu in the presence of glutathione (GSH). In vivo experiments demonstrated that this nanoplatform exhibits remarkable cell-killing efficiency by generating lethal reactive oxygen species (ROS) and mediating cuproptosis. In addition, DCM@GDY-CuMOF@DOX effectively suppresses tumor growth in vivo without causing any apparent side effects. The constructed DCM@GDY-CuMOF@DOX nanoplatform integrates tumor targeting, drug-responsive release and combination with cuproptosis and chemodynamic therapy, offering insights for further biomedical research on efficient PCa treatment.

Lymph nodes (LNs) play a pivotal role in colorectal cancer (CRC) progression and immunity, yet their molecular and functional diversity remains poorly understood. By analyzing 630 LNs and 88 primary tumors from 200 CRC patients across four independent cohorts using bulk and single-cell RNA sequencing, we identify four non-metastatic negative LNs (NLN) subtypes (NLN_C1-C4) exhibiting obviously different immune function and stromal expansion. NLN_C3/C4 are characterized by diminished T and B cell activity and fibroblast-driven fibrosis, with follicular dendritic cell loss contributing to B cell dysfunction. Immune checkpoint inhibitors partially reverse these effects, restoring FDC and B cell activity. LNs subtypes demonstrate heterogeneity across patients and within individuals, with higher NLN_C3/C4 proportions associated with advanced tumor stages, poorer survival, and recurrence. Here, we report LNs subtypes as critical manifestations of LN heterogeneity in CRC, providing a basis for improved clinical stratification and LN-targeted therapeutic strategies. Lymph nodes are primarily categorised into metastatic and non-metastatic. Here, the authors perform integrated bulk and single-cell RNA sequencing on lymph nodes from 200 patients with colorectal cancer and identify 4 non-metastatic lymph node subtypes.