Chronic periapical periodontitis (CAP), highly prevalent worldwide, has long been regarded as non-specific inflammation. Lipophilic Cutibacerium acnes (CA) persistence in host macrophages has emerged as the pathologic background of sarcoidosis and acne vulgaris. Here we report that intracellular persistence of CA in TREM2-macrophages plays a pathologic role in CAP. We observed persistent CA in macrophages in most CAP samples. Our CA clinical isolates persist in the cytosolic space of macrophages, retarding phagolysosomal degradation accompanied by NLRP3-dependent inflammatory response. Subcutaneous injection of those isolates in vivo recapitulates subcutaneous aggregation of CA-laden macrophages. By single cell RNA sequencing analysis of defined CAP samples, we found that CA in TREM2-macrophages drives exuberant lipid droplets formation, indicating that immune cells are potential lipid provider in CAP. Our observations elucidate the mechanistic link whereby TREM2-macrophages and altered lipid metabolism provide a lipid-rich niche for CA, contributing to the pathophysiology of CAP.

Long-term steroid use, though essential for treating eye diseases, can cause increased intraocular pressure (IOP) in susceptible individuals and may lead to steroid-induced glaucoma in a subset of patients. This study investigated the effect of bone morphogenetic protein-7 (BMP-7) on steroid-induced extracellular matrix (ECM) synthesis in human trabecular meshwork (TM) cells. We sought to explore the potential of BMP-7 as a protective agent against steroid-induced ECM accumulation in the TM. Human TM cells (HTMCs) were treated with either steroids alone or a combination of steroids and BMP-7 to compare their effects on ECM production. BMP-7, known for its transforming growth factor beta (TGF-β) antagonistic properties, was administered using a micellized protein transduction domain (mPTD)-fused BMP-7 polypeptide to enhance activity. Gene expression analysis was conducted to identify specific genes involved in ECM regulation. BMP-7 effectively inhibited steroid-induced ECM accumulation in HTMCs. There was a significant reduction in ECM production in the steroid and BMP-7 co-treated group compared with that in the steroid-only group. Furthermore, several genes involved in ECM regulation were identified in the co-treatment, underscoring BMP-7's potential role in modulating ECM metabolism. These findings demonstrate that BMP-7 exerts protective, anti-fibrotic effects in HTMCs by inhibiting steroid-induced ECM synthesis. BMP-7 may serve as a promising therapeutic target for preventing or treating steroid-induced glaucoma by maintaining normal aqueous humor outflow and preventing IOP elevation.

AbstractBackgroundBone morphogenetic protein-7 (BMP-7) antagonises transforming growth factor-β (TGF-β). This study investigated the ability of a prodrug BMP-7, designed as micelle nanoparticles for nasal inhalation, to ameliorate pulmonary fibrosis in a bleomycin (BLM)-induced murine model.Materials and MethodsFluorescently labelled BMP-7 was delivered to murine lungs via nasal inhalation. Thirty-eight C57BL/6J mice were divided into three groups: control, BLM and BLM with prodrug BMP-7. We then administered the prodrug BMP-7 and vehicle nasally every 72 hours for 21 days. Single-cell RNA sequencing was performed on bronchoalveolar lavage fluid (BALF) from 18 mice, divided into four groups: control, prodrug BMP-7 alone, BLM and BLM with prodrug BMP-7, to assess effects on alveolar macrophages (AM). The expression of ApoE+ AM was compared between normal and idiopathic pulmonary fibrosis (IPF) patients.ResultsThe prodrug BMP-7 group showed reduced BALF inflammatory cells and significant fibrosis reduction compared to the BLM group. Western blot showed decreased levels of collagen I, α-SMA and fibronectin in the prodrug BMP-7 group, along with downregulation of TGF-β/SMAD signalling. ELISA indicated decreased levels of chemokines CXCL10 and CXCL2 in tissue and BALF. Single-cell RNA sequencing revealed a significant increase in bone marrow-derived ApoE+ AM in the BLM group, which was reduced with prodrug BMP-7. Additionally, ApoE+ expression was higher in IPF patients compared to controls.ConclusionsProdrug BMP-7 shows potential as a therapeutic agent for pulmonary fibrosis by modulating ApoE+ AM.

Background:Approximately 30% of diabetic patients develop diabetic nephropathy, a representative microvascular complication. Although the etiological mechanism has not yet been fully elucidated, renal tubular damage by hyperglycemia-induced expression of transforming growth factor-β (TGF-β) is known to be involved. Recently, a new type of cell death by iron metabolism called ferroptosis was reported to be involved in kidney damage in animal models of diabetic nephropathy, which could be induced by TGF-β. Bone morphogenetic protein-7 (BMP7) is a well-known antagonist of TGF-β inhibiting TGF-β-induced fibrosis in many organs. Further, BMP7 has been reported to play a role in the regeneration of pancreatic beta cells in diabetic animal models.Methods:We used protein transduction domain (PTD)-fused BMP7 in micelles (mPTD-BMP7) for long-lasting in vivo effects and effective in vitro transduction and secretion.Results:mPTD-BMP7 successfully accelerated the regeneration of diabetic pancreas and impeded progression to diabetic nephropathy. With the administration of mPTD-BMP7, clinical parameters and representative markers of pancreatic damage were alleviated in a mouse model of streptozotocin-induced diabetes. It not only inhibited the downstream genes of TGF-β but also attenuated ferroptosis in the kidney of the diabetic mouse and TGF-β-stimulated rat kidney tubular cells.Conclusion:BMP7 impedes the progression of diabetic nephropathy by inhibiting the canonical TGF-β pathway, attenuating ferroptosis, and helping regenerate diabetic pancreas.

The clinical application of growth factors such as recombinant human bone morphogenetic protein-2 (rh-BMP-2), for functional bone regeneration remains challenging due to limited in vivo efficacy and adverse effects of previous modalities. To overcome the instability and short half-life of rh-BMP-2 in vivo, we developed a novel osteogenic supplement by fusing a protein transduction domain (PTD) with BMP-2, effectively creating a prodrug of BMP-2. In this study, we first created an improved PTD-BMP-2 formulation using lipid nanoparticle (LNP) micellization, resulting in downsizing from micrometer to nanometer scale and achieving a more even distribution. The micellized PTD-BMP-2 (mPTD-BMP-2) demonstrated improved distribution and aggregation profiles. As a prodrug of BMP-2, mPTD-BMP-2 successfully activated Smad1/5/8 and induced mineralization with osteogenic gene induction in vitro. In vivo pharmacokinetic analysis revealed that mPTD-BMP-2 had a much more stable pharmacokinetic profile than rh-BMP-2, with a 7.5-fold longer half-life. The in vivo BMP-responsive element (BRE) reporter system was also successfully activated by mPTD-BMP-2. In the in vivo rat tibia distraction osteogenesis (DO) model, micro-computed tomography (micro-CT) scan findings indicated that mPTD-BMP-2 significantly increased bone volume, bone surface, axis moment of inertia (MOI), and polar MOI. Furthermore, it increased the expression of osteogenesis-related genes, and induced bone maturation histologically. Based on these findings, mPTD-BMP-2 could be a promising candidate for the next-generation osteogenesis drug to promote new bone formation in DO surgery. STATEMENT OF SIGNIFICANCE: This study introduces micellized bone morphogenetic protein-2 (mPTD-BMP-2), a next-generation osteogenic supplement that combines protein transduction domain (PTD) and nano-sized micelle formulation technique to improve transduction efficiency and stability. The use of PTD represents a novel approach, and our results demonstrate the superiority of mPTD-BMP-2 over rh-BMP-2 in terms of in vivo pharmacokinetic profile and osteogenic potential, particularly in a rat tibial model of distraction osteogenesis. These findings have significant scientific impact and potential clinical applications in the treatment of bone defects that require distraction osteogenesis. By advancing the field of osteogenic supplements, our study has the potential to contribute to the development of more effective treatments for musculoskeletal disorders.

Decreased angiogenesis contributes to delayed wound healing in diabetic patients. Recombinant human bone morphogenetic protein-2 (rhBMP2) has also been demonstrated to promote angiogenesis. However, the short half-lives of soluble growth factors, including rhBMP2, limit their use in wound-healing applications. To address this limitation, we propose a novel delivery model using a protein transduction domain (PTD) formulated in a lipid nanoparticle (LNP). We aimed to determine whether a gelatin hydrogel dressing loaded with LNP-formulated PTD-BMP2 (LNP-PTD-BMP2) could enhance the angiogenic function of BMP2 and improve diabetic wound healing. In vitro, compared to the control and rhBMP2, LNP-PTD-BMP2 induced greater tube formation in human umbilical vein endothelial cells and increased the cell recruitment capacity of HaCaT cells. We inflicted large, full-thickness back skin wounds on streptozotocin-induced diabetic mice and applied gelatin hydrogel (GH) cross-linked by microbial transglutaminase containing rhBMP2, LNP-PTD-BMP2, or a control to these wounds. Wounds treated with LNP-PTD-BMP2-loaded GH exhibited enhanced wound closure, increased re-epithelialization rates, and higher collagen deposition than those with other treatments. Moreover, LNP-PTD-BMP2-loaded GH treatment resulted in more CD31- and α-SMA-positive cells, indicating greater neovascularization capacity than rhBMP2-loaded GH or GH treatments alone. Furthermore, in vivo near-infrared fluorescence revealed that LNP-PTD-BMP2 has a longer half-life than rhBMP2 and that BMP2 localizes around wounds. In conclusion, LNP-PTD-BMP2-loaded GH is a viable treatment option for diabetic wounds.

ABSTRACTA structural protein of SARS-CoV-2, nucleocapsid (N) protein is abundantly expressed during viral replication. The N protein is phosphorylated by glycogen synthase kinase (GSK)-3 on the serine/arginine (SR) rich motif located in disordered regions. Although phosphorylation by GSK-3β constitutes a critical event for viral replication, the molecular mechanism underlying N phosphorylation is not well understood. In this study, we found the putative alpha-helix L/FxxxL/AxxRL motif known as the GSK-3 interacting domain (GID), commonly found in many endogenous GSK-3β binding proteins, such as Axins, FRATs, WWOX and GSKIP. Indeed, N interacts with GSK-3β similarly to Axin, and Leu to Glu substitution of the GID abolished the interaction, with loss of N phosphorylation. Unlike with endogenous GID proteins, the N interaction neither disturbs endogenous GSK-3 activity nor regulates subsequent canonical Wnt activity and the Snail-EMT program. Notably, N abundance in SARS-CoV-2 is incomparably high compared to other coronaviruses, such as 229E, OC43 and HKU1. Compared to other coronaviruses, N harbors a CDK1 primed phosphorylation site and Gly-rich linker for enhanced phosphorylation by GSK-3β. Furthermore, we found that the S202R mutant found in Delta and R203K/G204R mutant found in the Omicron variant allows increased abundance and hyper-phosphorylation of N. Our observations suggest that the emergence of GID and mutations for increased phosphorylation in N may have contributed to the emergence of SARS-CoV-2 and evolution of variants, respectively. Further study, especially in a BSL3-equipped facility, is required to elucidate the functional importance of GID and N phosphorylation in SARS-CoV-2 and variants.

Decreased angiogenesis contributes to delayed wound healing in diabetic patients. Recombinant human bone morphogenetic protein-2 (rhBMP2), which has been approved by the FDA for inducing bone regeneration, has also been shown to promote angiogenesis. However, the short half-lives of soluble growth factors, including rhBMP2, limit their use in wound-healing applications. To overcome this limitation, we propose a novel delivery model utilizing a protein transduction domain (PTD) formulated in lipid nanoparticle (LNP). We aimed to determine whether a gelatin hydrogel dressing loaded with LNP formulated PTD-BMP2 (LNP-PTD-BMP2) can improve the angiogenic function of BMP2 and improve diabetic wound healing. In vitro, we found that, compared to the control and rhBMP2, LNP-PTD-BMP2 induced higher tube formation of human umbilical vein endothelial cells and increased the cell recruitment capacity of HaCaT cells in a scratch wound assay. Large, full-thickness back skin wounds were inflicted on streptozotocin-induced diabetic mice, and gelatin hydrogel (GH) cross-linked by microbial transglutaminase containing rhBMP2, LNP-PTD-BMP2, or a control was applied to these wounds. Wounds treated with LNP-PTD-BMP2-loaded GH exhibited enhanced wound closure, increased re-epithelialization rates, and higher collagen deposition than those treated with rhBMP2-loaded GH or only GH. In an immunofluorescence study, LNP-PTD-BMP2-loaded GH treatment resulted in more CD31- and α-SMA-positive cells, thus demonstrating a higher neovascularization capacity than rhBMP2-loaded GH or only GH treatments. Additionally, in vivo near-infrared fluorescent images showed that LNP-PTD-BMP2 has a longer half-life than rhBMP2 and that BMP2 localizes around wounds. These findings suggest that LNP-PTD-BMP2-loaded GH is a viable treatment for diabetic wounds.

Bone morphogenetic protein-7 (BMP-7) antagonizes transforming growth factor-β (TGF-β), which is critically involved in liver fibrogenesis. Here, we designed a micelle formulation consisting of a protein transduction domain (PTD) fused BMP-7 polypeptide (mPTD-BMP-7) to enhance endocytic delivery, and investigated its ability to ameliorate liver fibrosis. The mPTD-BMP-7 formulation was efficiently delivered into cells via endocytosis, where it inhibited TGF-β mediated epithelial-mesenchymal transition. After successfully demonstrating delivery of fluorescently labeled mPTD-BMP-7 into the murine liver in vivo, we tested the mPTD-BMP-7 formulation in a murine liver fibrosis model, developed by repeated intraperitoneal injection of hepatotoxic carbon tetrachloride, twice weekly from 4 to 16 weeks. mPTD-BMP-7 effects were tested by injecting the mPTD-BMP-7 formulation (or vehicle control) into the lateral tail at a dose of 50 (n=8) or 500 μg/kg (n=10), also twice per week from 4 to 16 weeks. Vehicle-treated control mice developed fibrous septa surrounding the liver parenchyma and marked portal-to-portal bridging with occasional nodules, whereas mice treated with mPTD-BMP-7 showed only fibrous expansion of some portal areas, with or without short fibrous septa. Using the Ishak scoring system, we found that the fibrotic burden was significantly lower in mPTD-BMP-7 treated mice than in control mice (all P<0.001). Treatment with mPTD-BMP-7 protected tight junctions between hepatocytes and reduced extracellular matrix protein levels. It also significantly decreased mRNA levels of collagen 1A, smooth muscle α-actin, and connective tissue growth factor compared with that in control mice (all P<0.001). Collectively, out results indicate that mPTD-BMP-7, a prodrug formulation of BMP-7, ameliorates liver fibrosis by suppressing the TGF-β signaling pathway in a murine liver fibrosis model.

African swine fever virus (ASFV) causes a highly contagious and severe hemorrhagic viral disease with high mortality in domestic pigs of all ages. Although the virus is harmless to humans, the ongoing ASFV epidemic could have severe economic consequences for global food security. Recent studies have found a few antiviral agents that can inhibit ASFV infections. However, currently, there are no vaccines or antiviral drugs. Hence, there is an urgent need to identify new drugs to treat ASFV. Based on the structural information data on the targets of ASFV, we used molecular docking and machine learning models to identify novel antiviral agents. We confirmed that compounds with high affinity present in the region of interest belonged to subsets in the chemical space using principal component analysis and k-means clustering in molecular docking studies of FDA-approved drugs. These methods predicted pentagastrin as a potential antiviral drug against ASFVs. Finally, it was also observed that the compound had an inhibitory effect on AsfvPolX activity. Results from the present study suggest that molecular docking and machine learning models can play an important role in identifying potential antiviral drugs against ASFVs.

Although protein-protein interactions (PPIs) have emerged as the basis of potential new therapeutic approaches, targeting intracellular PPIs with small molecule inhibitors is conventionally considered highly challenging. Driven by increasing research efforts, success rates have increased significantly in recent years. In this study, we analyze the physicochemical properties of 9351 non-redundant inhibitors present in the iPPI-DB and TIMBAL databases to define a computational model for active compounds acting against PPI targets. Principle component analysis (PCA) and k-means clustering were used to identify plausible PPI targets in regions of interest in the active group in the chemical space between active and inactive iPPI compounds. Notably, the uniquely defined active group exhibited distinct differences in activity compared with other active compounds. These results demonstrate that active compounds with regions of interest in the chemical space may be expected to provide insights into potential PPI inhibitors for particular protein targets.

Figure 1.The life cycle of SARS-CoV-2.ACE-2, angiotensin converting enzyme; Mpro, main protease; RdRp, RNA-dependent RNA polymerase.

Ischemia-reperfusion injury is a major cause of acute kidney injury. Recent studies on the pathophysiology of ischemia-reperfusion-induced acute kidney injury showed that immunologic responses significantly affect kidney ischemia-reperfusion injury and repair. Nuclear factor (NF)-ĸB signaling, which controls cytokine production and cell survival, is significantly involved in ischemia-reperfusion-induced acute kidney injury, and its inhibition can ameliorate ischemic acute kidney injury. Using EXPLOR, a novel, optogenetically engineered exosome technology, we successfully delivered the exosomal super-repressor inhibitor of NF-ĸB (Exo-srIĸB) into B6 wild type mice before/after kidney ischemia-reperfusion surgery, and compared outcomes with those of a control exosome (Exo-Naïve)-injected group. Exo-srIĸB treatment resulted in lower levels of serum blood urea nitrogen, creatinine, and neutrophil gelatinase-associated lipocalin in post-ischemic mice than in the Exo-Naïve treatment group. Systemic delivery of Exo-srIĸB decreased NF-ĸB activity in post-ischemic kidneys and reduced apoptosis. Post-ischemic kidneys showed decreased gene expression of pro-inflammatory cytokines and adhesion molecules with Exo-srIĸB treatment as compared with the control. Intravital imaging confirmed the uptake of exosomes in neutrophils and macrophages. Exo-srIĸB treatment also significantly affected post-ischemic kidney immune cell populations, lowering neutrophil, monocyte/macrophage, and T cell frequencies than those in the control. Thus, modulation of NF-ĸB signaling through exosomal delivery can be used as a novel therapeutic method for ischemia-reperfusion-induced acute kidney injury.

The Wnt and Hippo pathways are tightly coordinated and understanding their reciprocal regulation may provide a novel therapeutic strategy for cancer. Anti-helminthic niclosamide is an effective inhibitor of Wnt and is now in a phase II trial for advanced colorectal cancer (CRC) patients. We found that Axin2, an authentic target gene of canonical Wnt, acts as aYAP phosphorylation activator in APC-mutated CRC. While niclosamide effectively suppresses Wnt, it also inhibits Hippo, limiting its therapeutic potential for CRC. To overcome this limitation, we utilized metformin, a clinically available AMPK activator. This combinatory approach not only suppresses canonical Wnt activity, but also inhibits YAP activity in CRC cancer cells and in patient-derived cancer organoid through the suppression of cancer stemness. Further, combinatory oral administration suppressed in vivo tumorigenesis and the cancer progression of APC-MIN mice models. Our observations provide not only a reciprocal link between Wnt and Hippo, but also clinically available novel therapeutics that are able to target Wnt and YAP in APC-mutated CRC.

The epithelial-mesenchymal transition (EMT) comprises an important biological mechanism not only for cancer progression but also in the therapeutic resistance of cancer cells. While the importance of the protein abundance of EMT-inducers, such as Snail (SNAI1) and Zeb1 (ZEB1), during EMT progression is clear, the reciprocal interactions between the untranslated regions (UTRs) of EMT-inducers via a competing endogenous RNA (ceRNA) network have received little attention. In this study, we found a synchronized transcript abundance of Snail and Zeb1 mediated by a non-coding RNA network in colorectal cancer (CRC). Importantly, the trans-regulatory ceRNA network in the UTRs of EMT inducers is mediated by competition between tumor suppressive miRNA-34 (miR-34) and miRNA-200 (miR-200). Furthermore, the ceRNA network consisting of the UTRs of EMT inducers and tumor suppressive miRs is functional in the EMT phenotype and therapeutic resistance of colon cancer. In The Cancer Genome Atlas (TCGA) samples, we also found genome-wide ceRNA gene sets regulated by miR-34a and miR-200 in colorectal cancer. These results indicate that the ceRNA networks regulated by the reciprocal interaction between EMT gene UTRs and tumor suppressive miRs are functional in CRC progression and therapeutic resistance.

This study reports a mechanism of mitochondrial ATP generation whereby EMT-inducer Snail controls ACC2 abundance and subsequent fatty acid oxidation to support cancer survival under starvation conditions. Despite the importance of mitochondrial fatty acid oxidation (FAO) in cancer metabolism, the biological mechanisms responsible for the FAO in cancer and therapeutic intervention based on catabolic metabolism are not well defined. In this study, we observe that Snail (SNAI1), a key transcriptional repressor of epithelial–mesenchymal transition, enhances catabolic FAO, allowing pro-survival of breast cancer cells in a starved environment. Mechanistically, Snail suppresses mitochondrial ACC2 (ACACB) by binding to a series of E-boxes located in its proximal promoter, resulting in decreased malonyl-CoA level. Malonyl-CoA being a well-known endogenous inhibitor of fatty acid transporter carnitine palmitoyltransferase 1 (CPT1), the suppression of ACC2 by Snail activates CPT1-dependent FAO, generating ATP and decreasing NADPH consumption. Importantly, combinatorial pharmacologic inhibition of pentose phosphate pathway and FAO with clinically available drugs efficiently reverts Snail-mediated metabolic reprogramming and suppresses in vivo metastatic progression of breast cancer cells. Our observations provide not only a mechanistic link between epithelial–mesenchymal transition and catabolic rewiring but also a novel catabolism-based therapeutic approach for inhibition of cancer progression.

Glioblastoma (GBM) is the most aggressive type of brain tumor and has poor survival outcomes, even after a combination of surgery, radiotherapy, and chemotherapy. Temozolomide is the only agent that has been shown to be effective against GBM, suggesting that combination of temozolomide with other agents may be more effective. Niclosamide, an FDA approved anthelmintic agent, has shown anti-cancer effects against human colon, breast, prostate cancers as well as GBM. However, the efficacy of the combination of niclosamide with temozolomide against GBM tumorspheres (TSs) has not been determined. We hypothesized that the combined treatment could effectively suppress GBM TSs. GBM TSs (TS15-88, GSC11) were treated with niclosamide and/or temozolomide. Combined effects of two drugs were evaluated by measuring viability, neurosphere formation, and 3D-invasion in collagen matrix. Transcriptional profiles of GBM TS were analyzed using RNA sequencing. In vivo anticancer efficacy of combined drugs was tested in a mouse orthotopic xenograft model. Combination treatment of niclosamide and temozolomide significantly inhibited the cell viability, stemness, and invasive properties of GBM TSs. This combined treatment significantly down-regulated the expression of epithelial mesenchymal transition-related markers, Zeb1, N-cadherin, and β-catenin. The combined treatment also significantly decreased tumor growth in orthotopic xenograft models. The combination of niclosamide and temozolomide effectively decreased the stemness and invasive properties of GBM TSs, suggesting that this regimen may be therapeutically effective in treating patients with GBM.

As extracellular vesicles that play an active role in intercellular communication by transferring cellular materials to recipient cells, exosomes offer great potential as a natural therapeutic drug delivery vehicle. The inflammatory responses in various disease models can be attenuated through introduction of super-repressor IκB (srIκB), which is the dominant active form of IκBα and can inhibit translocation of nuclear factor κB into the nucleus. An optogenetically engineered exosome system (EXPLOR) that we previously developed was implemented for loading a large amount of srIκB into exosomes. We showed that intraperitoneal injection of purified srIκB-loaded exosomes (Exo-srIκBs) attenuates mortality and systemic inflammation in septic mouse models. In a biodistribution study, Exo-srIκBs were observed mainly in the neutrophils, and in monocytes to a lesser extent, in the spleens and livers of mice. Moreover, we found that Exo-srIκB alleviates inflammatory responses in monocytic THP-1 cells and human umbilical vein endothelial cells.

While the bone morphogenetic protein‐7 (BMP‐7) is a well‐known therapeutic growth factor reverting many fibrotic diseases, including peritoneal fibrosis by peritoneal dialysis (PD), soluble growth factors are largely limited in clinical applications owing to their short half‐life in clinical settings. Recently, we developed a novel drug delivery model using protein transduction domains (PTD) overcoming limitation of soluble recombinant proteins, including bone morphogenetic protein‐7 (BMP‐7). This study aims at evaluating the therapeutic effects of PTD‐BMP‐7 consisted of PTD and full‐length BMP‐7 on epithelial‐mesenchymal transition (EMT)‐related fibrosis. Human peritoneal mesothelial cells (HPMCs) were then treated with TGF‐β1 or TGF‐β1 + PTD‐BMP‐7. Peritoneal dialysis (PD) catheters were inserted into Sprague‐Dawley rats, and these rats were infused intra‐peritoneally with saline, peritoneal dialysis fluid (PDF) or PDF + PTD‐BMP‐7. In vitro, TGF‐β1 treatment significantly increased fibronectin, type I collagen, α‐SMA and Snail expression, while reducing E‐cadherin expression in HPMCs ( P < .001). PTD‐BMP‐7 treatment ameliorated TGF‐β1‐induced fibronectin, type I collagen, α‐SMA and Snail expression, and restored E‐cadherin expression in HPMCs ( P < .001). In vivo, the expressions of EMT‐related molecules and the thickness of the sub‐mesothelial layer were significantly increased in the peritoneum of rats treated with PDF, and these changes were significantly abrogated by the intra‐peritoneal administration of PTD‐BMP‐7. PTD‐BMP‐7 treatment significantly inhibited the progression of established PD fibrosis. These findings suggest that PTD‐BMP‐7, as a prodrug of BMP‐7, can be an effective therapeutic agent for peritoneal fibrosis in PD patients.