gp120-derived amyloidogenic peptides form amyloid fibrils that increase HIV-1 infectivity.

Apart from mediating viral entry, the function of the free HIV-1 envelope protein (gp120) has yet to be elucidated. Our group previously showed that EP2 derived from one ß-strand in gp120 can form amyloid fibrils that increase HIV-1 infectivity. Importantly, gp120 contains ~30 ß-strands. We examined whether gp120 might serve as a precursor protein for the proteolytic release of amyloidogenic fragments that form amyloid fibrils, thereby promoting viral infection. Peptide array scanning, enzyme degradation assays, and viral infection experiments in vitro confirmed that many ß-stranded peptides derived from gp120 can indeed form amyloid fibrils that increase HIV-1 infectivity. These gp120-derived amyloidogenic peptides, or GAPs, which were confirmed to form amyloid fibrils, were termed gp120-derived enhancers of viral infection (GEVIs). GEVIs specifically capture HIV-1 virions and promote their attachment to target cells, thereby increasing HIV-1 infectivity. Different GAPs can cross-interact to form heterogeneous fibrils that retain the ability to increase HIV-1 infectivity. GEVIs even suppressed the antiviral activity of a panel of antiretroviral agents. Notably, endogenous GAPs and GEVIs were found in the lymphatic fluid, lymph nodes, and cerebrospinal fluid (CSF) of AIDS patients in vivo. Overall, gp120-derived amyloid fibrils might play a crucial role in the process of HIV-1 infectivity and thus represent novel targets for anti-HIV therapeutics.

The substitution sites of hydroxyl and galloyl groups determine the inhibitory activity of human pancreatic α-amylase in twelve tea polyphenol monomers.

Tea polyphenols have been reported as potential α-amylase inhibitors. However, the quantitative structure-activity relationship (QSAR) between tea polyphenols and human pancreas α-amylase (HPA) is not well understood. Herein, the inhibitory effect of twelve tea polyphenol monomers on HPA was investigated in terms of inhibitory activity, as well as QSAR analysis and interaction mechanism. The results revealed that the HPA inhibitory activity of theaflavins (TFs), especially theaflavin-3'-gallate (TF-3'-G, IC50: 0.313 mg/mL), was much stronger than that of catechins (IC50: 18.387-458.932 mg/mL). The QSAR analysis demonstrated that the determinant for the inhibitory activity of HPA was not the number of hydroxyl and galloyl groups in tea polyphenol monomers, while the substitution sites of these groups potentially might play a more important role in modulating the inhibitory activity. The inhibition kinetics and molecular docking revealed that TF-3'-G as a mixed-type inhibitor had the lowest inhibition constant and bound to the active sites of HPA with the lowest binding energy (-7.74 kcal/mol). These findings could provide valuable insights into the structures-activity relationships between tea polyphenols and the HPA inhibitors.

mDia formins form hetero-oligomers and cooperatively maintain murine hematopoiesis.

mDia formin proteins regulate the dynamics and organization of the cytoskeleton through their linear actin nucleation and polymerization activities. We previously showed that mDia1 deficiency leads to aberrant innate immune activation and induces myelodysplasia in a mouse model, and mDia2 regulates enucleation and cytokinesis of erythroblasts and the engraftment of hematopoietic stem and progenitor cells (HSPCs). However, whether and how mDia formins interplay and regulate hematopoiesis under physiological and stress conditions remains unknown. Here, we found that both mDia1 and mDia2 are required for HSPC regeneration under stress, such as serial plating, aging, and reconstitution after myeloid ablation. We showed that mDia1 and mDia2 form hetero-oligomers through the interactions between mDia1 GBD-DID and mDia2 DAD domains. Double knockout of mDia1 and mDia2 in hematopoietic cells synergistically impaired the filamentous actin network and serum response factor-involved transcriptional signaling, which led to declined HSPCs, severe anemia, and significant mortality in neonates and newborn mice. Our data demonstrate the potential roles of mDia hetero-oligomerization and their non-rodent functions in the regulation of HSPCs activity and orchestration of hematopoiesis.

Hypoxia-cleavable and specific targeted nanomedicine delivers epigenetic drugs for enhanced treatment of breast cancer and bone metastasis.

Breast cancer bone metastasis has become a common cancer type that still lacks an effective treatment method. Although epigenetic drugs have demonstrated promise in cancer therapy, their nontargeted accumulation and drug resistance remain nonnegligible limiting factors. Herein, we first found that icaritin had a strong synergistic effect with an epigenetic drug (JQ1) in the suppression of breast cancer, which could help to relieve drug resistance to JQ1. To improve tumor-targeted efficacy, we developed a hypoxia-cleavable, RGD peptide-modified poly(D,L-lactide-co-glycolide) (PLGA) nanoparticle (termed ARNP) for the targeted delivery of JQ1 and icaritin. The decoration of long cleavable PEG chains can shield RGD peptides during blood circulation and reduce cellular uptake at nonspecific sites. ARNP actively targets breast cancer cells via an RGD-αvß3 integrin interaction after PEG chain cleavage by responding to hypoxic tumor microenvironment. In vitro and in vivo assays revealed that ARNP exhibited good biodistribution and effectively suppressed primary tumor and bone metastasis. Meanwhile, ARNP could alleviate bone erosion to a certain extent. Furthermore, ARNP significantly inhibited pulmonary metastasis secondary to bone metastasis. The present study suggests that ARNP has great promise in the treatment of breast cancer and bone metastasis due to its simple and practical potential.

Colon targeted releases and uptakes of paclitaxel loaded in modified porous starch.

Hyaluronic acid can modify porous starch through cross-linking and hydrogen bonding, effectively achieving a paclitaxel entrapment efficiency of ∼92 % and drug loading of ∼23 %. In this study, the pores and intergranular gaps of porous starch were filled with paclitaxel under solvent volatilization, and the enrichment process and its characteristics were recorded using a microscope. The paclitaxel-loaded particles were coated with chitosan-phytic acid to target the colon. In vivo imaging in mice showed that the capsule released paclitaxel in the colon rather than in the upper digestive tract, and the paclitaxel distribution in the main organs at 24 h was significantly lower than that of raw paclitaxel. Hyaluronic acid-modified porous starch can target cancer cells. Cell internalization of paclitaxel mediated by hyaluronic acid was approximately 1.97 times that of raw paclitaxel, higher than that of receptor-shielded cells and cells incubated with unmodified carriers, as evidenced by the accumulation of fluorescent paclitaxel in the nucleus and marked cell apoptosis. The hyaluronic acid-modified porous starch system is an effective method for the high-load and targeted release of hydrophobic anticancer drugs.

Adsorption and Assembly of Octenyl Succinic Anhydride Starch/Chitosan Electrostatic Complexes at Oil-Water Interface.

Biopolymer electrostatic complexes are popular Pickering stabilizers whose structures greatly affect their interfacial properties. This study comprehensively demonstrated the interfacial adsorption and assembly of dissolved octenyl succinic anhydride (OSA) starch (OSA-D)/chitosan (CS) electrostatic complexes with different structures through complementary characterization methods. We found that compared with single-component systems, OSA-D/CS complexes exhibited significantly increased wetting stability and adsorption rate to the interface, which was reinforced by molecular dynamics simulations. Their soft structures and the entanglement of molecular chains led to the formation of thick and highly viscoelastic multilayer adsorbed films, which greatly resisted deformation against shearing forces. The adsorption and assembly of the complexes were strongly influenced by OSA-D/CS ratios and pH, which could be related to the different interfacial interaction strengths. Overall, the electrostatic complexation, structural characteristics, and interfacial properties of OSA-D/CS complexes were well related, thereby providing valuable information for the regulation of controlled interfaces and bulk system properties.

Clonal hematopoiesis and bone marrow inflammation.

Clonal hematopoiesis (CH) occurs in hematopoietic stem cells with increased risks of progressing to hematologic malignancies. CH mutations are predominantly found in aged populations and correlate with an increased incidence of cardiovascular and other diseases. Increased lines of evidence demonstrate that CH mutations are closely related to the inflammatory bone marrow microenvironment. In this review, we summarize the recent advances in this topic starting from the discovery of CH and its mutations. We focus on the most commonly mutated and well-studied genes in CH and their contributions to the innate immune responses and inflammatory signaling, especially in the hematopoietic cells of bone marrow. We also aimed to discuss the interrelationship between inflammatory bone marrow microenvironment and CH mutations. Finally, we provide our perspectives on the challenges in the field and possible future directions to help understand the pathophysiology of CH.

Initial experience with 161 extraperitoneal laparoscopic radical cystectomy procedures: Comparison with transabdominal laparoscopic radical cystectomy.

OBJECTIVES: There is substantial concern about traditional transperitoneal laparoscopic radical cystectomy (TLRC) due to multiple postoperative complications. In contrast, extraperitoneal laparoscopic radical cystectomy (ELRC) appears to cause a lower rate of morbidity. The present study aimed to compare the efficacy of ELRC and TLRC for bladder cancer (BCa). METHODS: The clinical data of patients undergoing laparoscopic radical cystectomy for BCa from April 2018 to October 2021 were retrospectively analyzed, as ELRC and TLRC groups. The postoperative follow-up data of 275 patients were collected and the incidence of postoperative complications and other perioperative outcomes were compared between the two groups. RESULTS: Surgery was successfully completed in all patients without conversion to open surgery. There was no significant difference in the duration of cystectomy surgery (67.32 ± 23.53 vs 72.17 ± 25.72 min, p = 0.106), intraoperative blood loss (178.06 ± 110.4 vs. 174.56 ± 127.40 ml, p = 0.413), or the number of lymph node dissection (15.1 ± 5.7 vs. 14.5 ± 5.1, p = 0.380) between the two groups. The length of stay (11.6 ± 3.8 vs 14.7 ± 5.6 d, p < 0.001), time to resume food intake after surgery (2.3 ± 0.9 vs 3.0 ± 1.3 d, p < 0.001), and the incidence of ileus (p < 0.001) in the ELRC group were significantly lower than in the TLRC group. CONCLUSIONS: ELRC is a safe procedure that can reduce the incidence of postoperative complications, shorten postoperative hospital stay, reduce the duration of recovery of patients, and, therefore, should be promoted.

Corynoxine suppresses pancreatic cancer growth primarily via ROS-p38 mediated cytostatic effects.

BACKGROUND: Pancreatic cancer is among the most common malignant tumours, and effective therapeutic strategies are still lacking. While Corynoxine (Cory) can induce autophagy in neuronal cells, it remains unclear whether Cory has anti-tumour activities against pancreatic cancer. METHODS: Two pancreatic cancer cell lines, Patu-8988 and Panc-1, were used. Effects of Cory were evaluated by cell viability analysis, EdU staining, TUNEL assay, colony formation assay, and flow cytometry. Quantitative PCR and Western blot were performed to analyse mRNA and protein levels, respectively. In vivo anti-tumour efficacy of Cory was determined by a xenograft model. RESULTS: Cory treatment inhibited cell proliferation, induced endoplasmic reticulum (ER) stress, and triggered apoptosis in the pancreatic cancer cell lines. CHOP knockdown-mediated inhibition of ER stress alleviated the Cory-induced apoptosis but showed a limited effect on cell viability. Cory induced cell death partially via promoting reactive oxygen species (ROS) production and activating p38 signalling. Pretreatment with ROS scavenger N-acetylcysteine and p38 inhibitor SB203580 relieved the Cory-induced inhibition on cell growth. Cory remarkably blocked pancreatic tumour growth in vivo. CONCLUSIONS: Cory exerts an anti-tumour effect on pancreatic cancer primarily via ROS-p38-mediated cytostatic effects. Cory may serve as a promising therapeutic agent for pancreatic cancer.

Bone marrow-confined IL-6 signaling mediates the progression of myelodysplastic syndromes to acute myeloid leukemia.

Myelodysplastic syndromes (MDS) are age-related myeloid neoplasms with increased risk of progression to acute myeloid leukemia (AML). The mechanisms of transformation of MDS to AML are poorly understood, especially in relation to the aging microenvironment. We previously established an mDia1/miR-146a double knockout (DKO) mouse model phenocopying MDS. These mice develop age-related pancytopenia with oversecretion of proinflammatory cytokines. Here, we found that most of the DKO mice underwent leukemic transformation at 12-14 months of age. These mice showed myeloblast replacement of fibrotic bone marrow and widespread leukemic infiltration. Strikingly, depletion of IL-6 in these mice largely rescued the leukemic transformation and markedly extended survival. Single-cell RNA sequencing analyses revealed that DKO leukemic mice had increased monocytic blasts that were reduced with IL-6 knockout. We further revealed that the levels of surface and soluble IL-6 receptor (IL-6R) in the bone marrow were significantly increased in high-risk MDS patients. Similarly, IL-6R was also highly expressed in older DKO mice. Blocking of IL-6 signaling significantly ameliorated AML progression in the DKO model and clonogenicity of CD34-positive cells from MDS patients. Our study establishes a mouse model of progression of age-related MDS to AML and indicates the clinical significance of targeting IL-6 signaling in treating high-risk MDS.

Progress and prospects of modified starch-based carriers in anticancer drug delivery.

Recently, the role of starch-based carrier systems in anticancer drug delivery has gained considerable attention. Although there are same anticancer drugs, difference in their formulations account for unique therapeutic effects. However, the exploration on the effect-enhancing of anticancer drugs and their loading system by modified starch from the perspective of carrier regulation is still limited. Moreover, research on the reduced toxicity of the anticancer drugs due to modified starch as the drug carrier mediated by the intestinal microenvironment is lacking, but worth exploring. In this review, we examined the effect of modified starch on the loading and release properties of anticancer drugs, and the effect of resistant starch and its metabolites on intestinal microecology during inflammation. Particularly, the interactions between modified starch and drugs, and the effect of resistant starch on gene expression, protein secretion, and inflammatory factors were discussed. The findings of this review could serve as reference for the development of anticancer drug carriers in the future.

Cancer bone metastases and nanotechnology-based treatment strategies.

INTRODUCTION: Bone metastases have gradually been recognized as common metastases that affect patient quality of life and survival due to the increased incidence of primary tumors. However, there is still a lack of effective clinical treatment methods for bone metastases because of their particularity and complexity. Nanomedicine provides a new strategy for the treatment of bone metastases and shows great therapeutic potential. Thus, it is important to review the latest nanomedicine treatments for bone metastases. AREAS COVERED: This review introduces the mechanistic relationships of bone metastases and summarizes nanotechnology-based treatments of bone metastases according to targeting strategies. EXPERT OPINION: As we start to understand the mechanisms that enable bone metastases, we can better develop nanomedicine treatments. However, many of the mechanisms behind bone metastasis remain unclear. The application of nanomedicine shows promising anti-bone metastasis efficacy and helps to explore the pathogenesis of bone metastases. The optimized construction of nanomedicine according to bone metastatic properties is crucial to ensure the desired anti-bone metastasis efficacy and good biosafety. Therefore, the transition from bench to bedside still requires continued exploration.

Effects of different gelatinization degrees of starch in potato flour on the quality of steamed bread.

The effect of four kinds of potato flour with different gelatinization degrees on the quality of steam bread was investigated in the present study. Results showed that medium-well flour (MWF) and potato flakes (PF) steamed bread, particularly MWF steamed bread, possessed the desired product properties liked by consumers. The MWF steamed bread had the highest appearance score (42.78) and total sensory evaluation score (81.60), and the PF steamed bread exhibited the highest specific volume (1.84 mL/g) and taste score (43.05). An increase in the degree of potato flour gelatinization led to an increase in dough gas retention coefficient from 80.20 mL/100 mL to 85.17 mL/100 mL and a more uniform and dense dough microstructure. During dough preparation, the increased gelatinization degree of potato flours enhanced the hydroscopicity competition between potato starch and gluten, resulting in a flocculent gluten network and increased potato starch volume during steaming. During steaming, steamed bread with higher gelatinization degree of potato flour formed a homogenous and dense starch gel-gluten double network, making them softer with more uniform gas cells and larger specific volume. Thus, this study provides a perspective of the effect of starch gelatinization on steamed bread quality.

A Matrigel-based 3D construct of SH-SY5Y cells models the α-synuclein pathologies of Parkinson's disease.

Parkinson's disease (PD) is associated with α-synuclein-based Lewy body pathology, which has been difficult to observe in conventional two-dimensional (2D) cell culture and even in animal models. We herein aimed to develop a three-dimensional (3D) cellular model of PD to recapitulate the α-synuclein pathologies. All-trans-retinoic acid-differentiated human SH-SY5Y cells and Matrigel were optimized for 3D construction. The 3D cultured cells displayed higher tyrosine hydroxylase expression than 2D cells and improved dopaminergic-like phenotypes, as suggested by RNA-sequencing analyses. Multiple forms of α-synuclein, including monomer, and low- and high-molecular mass oligomers, were differentially present in the 2D and 3D cells, but mostly remained unchanged upon N-methyl-4-phenyl pyridine or rotenone treatment. Phosphorylated α-synuclein was accumulated, and detergent-insoluble α-synuclein fraction was observed, in the neurotoxin-treated 3D cells. Importantly, Lewy body-like inclusions were captured in the 3D system, including proteinase K-resistant α-synuclein aggregates, ubiquitin aggregation, and ß-amyloid and ß-sheet protein deposition. The study provides a unique and convenient 3D model of PD that recapitulates critical α-synuclein pathologies and should be useful in multiple PD-associated applications.

Rosmarinic Acid Decreases the Malignancy of Pancreatic Cancer Through Inhibiting Gli1 Signaling.

BACKGROUND: Rosmarinic acid (RA) has been shown to exert anti-tumor effects on various types of cancer. However, its roles in the treatment of pancreatic ductal adenocarcinoma (PDAC) and the underlying mechanisms remain elusive. PURPOSE: The present study aimed to investigate the therapeutic effects of RA on PDAC as well as the underlying mechanisms. STUDY DESIGN: Evaluation of the effects of RA on PDAC malignancy both in vitro and in vivo. METHODS: Cell counting kit 8 (CCK8) assay, colony formation assay, 5-Ethynyl-2'-deoxyuridine (EDU) incorporation assay, cell cycle analysis, and apoptosis assay were conducted to assess the inhibitory effect of RA on PDAC cell proliferation. Meanwhile, western blotting and RT-qPCR assay were performed to detect the target gene expression at protein and mRNA levels, respectively. Moreover, the in vivo anti-tumor activities of RA were assayed in an xenograft mouse model of PDAC. RESULTS: RA dramatically down-regulated Gli1 and its downstream targets. Further studies showed that RA prevents the nuclear translocation of Gli1, while promoting the degradation of cytosolic Gli1 via the proteasome pathway. Moreover, we observed that RA induced G1/S cell cycle arrest and apoptosis in the PDAC cells through regulating the expression of P21, P27, CDK2, Cyclin E, Bax, and Bcl-2, it inhibited the PDAC cell migration and invasion via E-cadherin and MMP-9. Notably, Gli1 overexpression markedly reversed the above RA-induced effects on PDAC cells, whereas Gli1 knockdown enhanced the effects. Additionally, the in vivo assays demonstrated that RA suppresses the tumor growth of PDAC presumably by inhibiting Gli1. CONCLUSION: We provided evidence that RA restrained the nuclear translocation of Gli1 and facilitates Gli1 degradation via proteasome pathway, reducing the malignancy of PDAC cells. These findings implicated RA as a therapeutic agent for PDAC.

TNF-α-mediated m6A modification of ELMO1 triggers directional migration of mesenchymal stem cell in ankylosing spondylitis.

Ankylosing spondylitis (AS) is a type of rheumatic disease characterized by chronic inflammation and pathological osteogenesis in the entheses. Previously, we demonstrated that enhanced osteogenic differentiation of MSC from AS patients (AS-MSC) resulted in pathological osteogenesis, and that during the enhanced osteogenic differentiation course, AS-MSC induced TNF-α-mediated local inflammation. However, whether TNF-α in turn affects AS-MSC remains unknown. Herein, we further demonstrate that a high-concentration TNF-α treatment triggers enhanced directional migration of AS-MSC in vitro and in vivo, which enforces AS pathogenesis. Mechanistically, TNF-α leads to increased expression of ELMO1 in AS-MSC, which is mediated by a METTL14 dependent m6A modification in ELMO1 3'UTR. Higher ELMO1 expression of AS-MSC is found in vivo in AS patients, and inhibiting ELMO1 in SKG mice produces therapeutic effects in this spondyloarthritis model. This study may provide insight into not only the pathogenesis but also clinical therapy for AS.

Periostin deficiency reduces diethylnitrosamine-induced liver cancer in mice by decreasing hepatic stellate cell activation and cancer cell proliferation.

Periostin is a critical extracellular regulator in the pathogenesis of liver disorders such as hepatosteatosis, non-alcoholic steatohepatitis, inflammation, and fibrosis. Periostin is also involved in the progression of hepatocellular carcinoma (HCC). However, the molecular mechanisms of periostin in hepatic stellate cell (HSC) activation and tumor cell proliferation in the pathogenesis of HCC remain largely unknown. We demonstrate that periostin is markedly upregulated in diethylnitrosamine (DEN)-induced mouse HCC tissues and that periostin knockout impairs DEN-induced HCC development. Periostin is predominantly derived from activated HSCs and periostin deficiency in HSCs impairs HSC activation and inhibits HSC-promoted HCC cell proliferation in vitro and tumor growth in vivo. Mechanistically, periostin promotes HSC activation through the integrin-FAK-STAT3-periostin pathway and augments HCC cell proliferation by activating ERK. There are positive correlations between periostin and HSC activation and cell proliferation in HCC clinical samples. Collectively, our findings demonstrate that HSC-derived periostin promotes HCC development by enhancing HSC activation through an autocrine periostin-integrin-FAK-STAT3-periostin circuit and by augmenting HCC cell proliferation via the ERK pathway in a paracrine manner. Thus, periostin is a multifaceted extracellular regulator in the development of HCC. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

IRF2-mediated upregulation of lncRNA HHAS1 facilitates the osteogenic differentiation of bone marrow-derived mesenchymal stem cells by acting as a competing endogenous RNA.

BACKGROUND: Mesenchymal stem cells (MSCs) are the major source of osteoblasts. Long noncoding RNAs (lncRNAs) are abundantly expressed RNAs that lack protein-coding potential and play an extensive regulatory role in cellular biological activities. However, the regulatory network of lncRNAs in MSC osteogenesis needs further investigation. METHODS: QRT-PCR, western blot, immunofluorescence, and immunohistochemistry assays were used to determine the levels of relevant genes. The osteogenic differentiation capability was evaluated by using Alizarin Red S (ARS) staining, alkaline phosphatase activity assays, hematoxylin & eosin staining or micro-CT. RNA fluorescence in situ hybridization (FISH) and RNAscope were used to detect HHAS1 expression in cells and bone tissue. A microarray assay was performed to identify differentially expressed microRNAs. RNA immunoprecipitation and RNA pull-down were used to explore the interactions between related proteins and nucleic acids. RESULTS: The level of lncRNA HHAS1 increased during bone marrow-derived MSC (BMSC) osteogenesis and was positively related to the levels of osteogenic genes and ARS intensity. HHAS1 was located in both the cytoplasm and the nucleus and was expressed in human bone tissue. HHAS1 facilitated BMSC osteogenic differentiation by downregulating miR-204-5p expression and enhancing the level of RUNX family transcription factor 2 (RUNX2). In addition, interferon regulatory factor 2 (IRF2) was increased during BMSC osteogenic differentiation and interacted with the promoter of HHAS1, which resulted in the transcriptional activation of HHAS1. Furthermore, IRF2 and HHAS1 helped improve bone defect repair in vivo. CONCLUSIONS: Our study identified a novel lncRNA, HHAS1, that facilitates BMSC osteogenic differentiation and proposed a role for the IRF2/HHAS1/miR-204-5p/RUNX2 axis in BMSC osteogenesis regulation. These findings help elucidate the regulatory network of BMSC osteogenesis and provide potential targets for clinical application.

The N6-methyladenosine demethylase ALKBH5 negatively regulates the osteogenic differentiation of mesenchymal stem cells through PRMT6.

N6-methyladenosine (m6A) modification is widespread in messenger RNAs and increasing evidence suggests the crucial roles of m6A in cell differentiation and tissue development. However, whether m6A modulates the osteogenic differentiation of mesenchymal stem cells (MSCs) has not been fully elucidated. Here we show that conditional knockout of the demethylase Alkbh5 in bone marrow MSCs strengthened bone mass in mice. Loss- and gain-of-function studies demonstrated that ALKBH5 negatively regulates the osteogenic differentiation of MSCs in vitro. At a mechanistic level, meRIP-seq and RNA-seq in MSCs following knockdown of ALKBH5 revealed changes in transcripts of PRMT6 containing consensus m6A motifs required for demethylation by ALKBH5. Furthermore, we found that ALKBH5 accelerates the degradation rate of PRMT6 mRNA in an m6A-dependent manner, and that the ALKBH5-PRMT6 axis regulates the osteogenesis of MSCs, mainly through activation of the PI3K/AKT pathway. Thus, our work reveals a different facet of the novel ALKBH5-PRMT6 axis that modulates the osteogenic differentiation of MSCs, which can serve as a target to improve the clinical use of MSCs.