2. Academic Validation
  3. Targeted Inhibition of CD74+ Macrophages by Luteolin via CEBPB/P65 Signaling Ameliorates Osteoarthritis Progression

Targeted Inhibition of CD74+ Macrophages by Luteolin via CEBPB/P65 Signaling Ameliorates Osteoarthritis Progression

  • Adv Sci (Weinh). 2025 Nov 21:e08472. doi: 10.1002/advs.202508472.
Rui Peng 1,  Bo Yu 2,  Lei Zhang 3,  Zhaowen Xue 4,  Lutian Yao 5,  Qingjun Yang 6,  Zitao Liu 7,  Sizhi Wu 8,  Yongquan Huang 7,  Xiaofei Zheng 4,  Huiying Guo 9,  Songwei Huan 9,  Tao Jiang 7,  Huajun Wang 4,  Yulong Wei 10,  Tao Gui 7
Affiliations

Affiliations

  • 1 Department of Bone and Joint Surgery, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
  • 2 Department of Orthopedics, Medical Innovation Technology Transformation Center of Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, China.
  • 3 Department of General Surgery, The Second Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, 233030, China.
  • 4 Department of Sports Medicine, The First Affiliated Hospital, Guangdong Provincial Key Laboratory of Speed Capability, The Guangzhou Key Laboratory of Precision Orthopedics and Regenerative Medicine, Jinan University, Guangzhou, Guangdong, 510630, China.
  • 5 Department of Orthopaedics, The First Hospital of China Medical University, Shenyang, 110001, China.
  • 6 College of Chinese Materia Medical, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
  • 7 State Key Laboratory of Traditional Chinese Medicine Syndrome/Department of Orthopaedics, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510120, China.
  • 8 Department of gerontology, Guangzhou First People's Hospital, Guangzhou, Guangdong, 510180, China.
  • 9 Department of Bone and Joint Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, 510632, China.
  • 10 Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
PMID: 41268703 DOI: 10.1002/advs.202508472
Abstract

Synovial inflammation represents a hallmark pathological process in osteoarthritis (OA), yet the cellular drivers orchestrating this response remain incompletely defined. Through single-cell transcriptomic profiling of human OA synovial tissues, a distinct subset of CD74⁺ macrophages is identified that displayed robust pro-inflammatory transcriptional signatures, underscoring the pivotal role of macrophages in shaping the inflammatory microenvironment. To explore therapeutic opportunities, computational ligand-target interaction analysis predicted luteolin as a high-affinity binder of CD74. Mechanistically, luteolin suppressed CD74 expression and disrupted the assembly of the CEBPB-p65 complex, thereby preventing p65 nuclear translocation and subsequent activation of the NF-κB signaling cascade in macrophages. To achieve targeted delivery, a nanoplatform MIF79-86-DS-PLGA-Luteolin (MDSPL) is engineered by conjugating MIF-mimetic peptides onto Reactive Oxygen Species (ROS)-responsive Poly(lactic-co-glycolic acid) (PLGA) nanoparticles, enabling selective recognition of CD74⁺ macrophages. In vivo, MDSPL exhibited superior efficacy over free luteolin in attenuating synovial inflammation and halting OA progression. Notably, early intervention with MDSPL yielded stronger chondroprotective effects than delayed administration, highlighting the therapeutic value of timely targeting of macrophage-driven inflammation. Collectively, these findings establish CD74⁺ macrophages as a pathogenic driver of OA-associated synovial inflammation and introduce MDSPL as a precision nanotherapeutic strategy with translational potential for OA management.

Keywords

CD74; CEBPB; luteolin; macrophage; osteoarthritis.

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