piENOX2 regulates ALKBH5-mediated Itga4 m6A modification to accelerate the progression of rheumatoid arthritis
Abstract Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovitis and presenting as symmetrical arthritis that primarily affects the small joints of the limbs. PIWI-interacting RNAs, a class of small noncoding RNAs, have garnered significant attention due to their critic...
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Nature Publishing Group
2025-07-01
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| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-025-01503-3 |
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| author | Naibo Feng Chungeng Liu Yuan Zhu Shuqiong Cai Yongheng Xie Zhenmin Wang Hua Wang Guozhi Xiao Houqing Long Songlin Peng |
| author_facet | Naibo Feng Chungeng Liu Yuan Zhu Shuqiong Cai Yongheng Xie Zhenmin Wang Hua Wang Guozhi Xiao Houqing Long Songlin Peng |
| author_sort | Naibo Feng |
| collection | DOAJ |
| description | Abstract Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovitis and presenting as symmetrical arthritis that primarily affects the small joints of the limbs. PIWI-interacting RNAs, a class of small noncoding RNAs, have garnered significant attention due to their critical involvement in various pathological conditions, including reproductive diseases, cancers and other disorders. Here we observe elevated levels of macrophage-derived piENOX2 in the synovial tissues of both patients with RA and mice with collagen-induced arthritis (CIA). It was found that transfection with a piENOX2 mimic promoted M1 macrophage polarization, while a piENOX2 inhibitor facilitated M2 polarization. In vivo, a piENOX2 inhibitor significantly alleviated disease progression, reduced systemic inflammation and preserved the integrity of articular cartilage in CIA mice. Mechanistic analyses indicated that the piENOX2 effects were due to its targeting Alkbh5 mRNA for degradation. In a Alkbh5 conditional-knockout mouse model of CIA, the therapeutic effects of a piENOX2 inhibitor, including inflammation suppression and cartilage protection, were reduced compared with control mice. A comprehensive analyses using methylated RNA immunoprecipitation sequencing and methylated RNA immunoprecipitation and quantitative PCR revealed that piENOX2 regulated ALKBH5-mediated m6A modification of Itga4 mRNA, thereby influencing macrophage polarization through the PI3K–AKT signaling pathway. These findings provide important insights into the complex roles of PIWI-interacting RNAs in RA progression and indicate potential avenues for therapeutic intervention. |
| format | Article |
| id | doaj-art-7b141e8aac5246c2ade3614d54f5d8c0 |
| institution | Kabale University |
| issn | 2092-6413 |
| language | English |
| publishDate | 2025-07-01 |
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| series | Experimental and Molecular Medicine |
| spelling | doaj-art-7b141e8aac5246c2ade3614d54f5d8c02025-08-20T04:01:43ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132025-07-015771579159210.1038/s12276-025-01503-3piENOX2 regulates ALKBH5-mediated Itga4 m6A modification to accelerate the progression of rheumatoid arthritisNaibo Feng0Chungeng Liu1Yuan Zhu2Shuqiong Cai3Yongheng Xie4Zhenmin Wang5Hua Wang6Guozhi Xiao7Houqing Long8Songlin Peng9Division of Spine, Department of Orthopedic Surgery, Shenzhen People’s Hospital, The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and TechnologyDivision of Spine, Department of Orthopedic Surgery, Shenzhen People’s Hospital, The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and TechnologyDivision of Spine, Department of Orthopedic Surgery, Shenzhen People’s Hospital, The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and TechnologyDivision of Spine, Department of Orthopedic Surgery, Shenzhen People’s Hospital, The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and TechnologyDivision of Spine, Department of Orthopedic Surgery, Shenzhen People’s Hospital, The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and TechnologyDivision of Spine, Department of Orthopedic Surgery, Shenzhen People’s Hospital, The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and TechnologyDepartment of Joint Surgery, Longhua Branch, Shenzhen People’s Hospital, The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and TechnologySchool of Medicine, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell MicroenvironmentDivision of Spine, Department of Orthopedic Surgery, Shenzhen People’s Hospital, The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and TechnologyDivision of Spine, Department of Orthopedic Surgery, Shenzhen People’s Hospital, The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and TechnologyAbstract Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovitis and presenting as symmetrical arthritis that primarily affects the small joints of the limbs. PIWI-interacting RNAs, a class of small noncoding RNAs, have garnered significant attention due to their critical involvement in various pathological conditions, including reproductive diseases, cancers and other disorders. Here we observe elevated levels of macrophage-derived piENOX2 in the synovial tissues of both patients with RA and mice with collagen-induced arthritis (CIA). It was found that transfection with a piENOX2 mimic promoted M1 macrophage polarization, while a piENOX2 inhibitor facilitated M2 polarization. In vivo, a piENOX2 inhibitor significantly alleviated disease progression, reduced systemic inflammation and preserved the integrity of articular cartilage in CIA mice. Mechanistic analyses indicated that the piENOX2 effects were due to its targeting Alkbh5 mRNA for degradation. In a Alkbh5 conditional-knockout mouse model of CIA, the therapeutic effects of a piENOX2 inhibitor, including inflammation suppression and cartilage protection, were reduced compared with control mice. A comprehensive analyses using methylated RNA immunoprecipitation sequencing and methylated RNA immunoprecipitation and quantitative PCR revealed that piENOX2 regulated ALKBH5-mediated m6A modification of Itga4 mRNA, thereby influencing macrophage polarization through the PI3K–AKT signaling pathway. These findings provide important insights into the complex roles of PIWI-interacting RNAs in RA progression and indicate potential avenues for therapeutic intervention.https://doi.org/10.1038/s12276-025-01503-3 |
| spellingShingle | Naibo Feng Chungeng Liu Yuan Zhu Shuqiong Cai Yongheng Xie Zhenmin Wang Hua Wang Guozhi Xiao Houqing Long Songlin Peng piENOX2 regulates ALKBH5-mediated Itga4 m6A modification to accelerate the progression of rheumatoid arthritis Experimental and Molecular Medicine |
| title | piENOX2 regulates ALKBH5-mediated Itga4 m6A modification to accelerate the progression of rheumatoid arthritis |
| title_full | piENOX2 regulates ALKBH5-mediated Itga4 m6A modification to accelerate the progression of rheumatoid arthritis |
| title_fullStr | piENOX2 regulates ALKBH5-mediated Itga4 m6A modification to accelerate the progression of rheumatoid arthritis |
| title_full_unstemmed | piENOX2 regulates ALKBH5-mediated Itga4 m6A modification to accelerate the progression of rheumatoid arthritis |
| title_short | piENOX2 regulates ALKBH5-mediated Itga4 m6A modification to accelerate the progression of rheumatoid arthritis |
| title_sort | pienox2 regulates alkbh5 mediated itga4 m6a modification to accelerate the progression of rheumatoid arthritis |
| url | https://doi.org/10.1038/s12276-025-01503-3 |
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