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已发表论文
在椎间盘退变中，TLR4 通过激活 NLRP12 诱导纤维环细胞发生 PANoptosis
Authors Zheng F, Cao L, Fu J, Luo M, Yue W, Ma Y, Chen B, Zhai Y, Liu C
Received 29 July 2025
Accepted for publication 23 November 2025
Published 1 December 2025 Volume 2025:18 Pages 16789—16804
DOI https://doi.org/10.2147/JIR.S556950
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Dr Ujjwol Risal
Feng Zheng,1,* Linhai Cao,2,* Jiawei Fu,2,* Menglin Luo,3 Wenbo Yue,1 Yulin Ma,1 Binghan Chen,4 Yu Zhai,2 Chenhao Liu1,2
1Department of Orthopedics, Qinghai Provincial People’s Hospital, Xining, Qinghai, People’s Republic of China; 2Department of Orthopedics, The Second Affiliated Hospital of Army Medical University, Chongqing, People’s Republic of China; 3Department of Laboratory, Chongqing Xiqu Hospital, Chongqing, People’s Republic of China; 4Department of Gastroenterology, People’s Hospital of Anguo, Baoding, Hebei, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Chenhao Liu, Department of Orthopedics, Qinghai Provincial People’s Hospital, Xining, Qinghai, 810007, People’s Republic of China, Email juggmore@163.com Yu Zhai, Department of Orthopedics, The Second Affiliated Hospital of Army Medical University, Chongqing, 400038, People’s Republic of China, Email zhaiyu9501@tmmu.edu.cn
Purpose: Intervertebral disc degeneration (IVDD), a common degenerative disorder, is characterized by chronic inflammation and progressive cell death. PANoptosis, an integrated form of programmed cell death that merges pyroptosis, apoptosis, and necroptosis, has recently emerged as a key contributor to degenerative diseases. Although Toll-like receptor 4 (TLR4) and NLRP12 are known to regulate inflammatory signaling and cell death, their roles in mediating annulus fibrosus cells (AFCs). This study investigated how the TLR4–NLRP12 axis regulates AFC PANoptosis and contributes to IVDD progression.
Methods: Single-cell RNA sequencing (scRNA-seq) profiled cell heterogeneity and PANoptosis-related signaling in healthy/degenerative annulus fibrosus (AF) tissues. An in vitro IVDD model was established by treating AFCs with TNF-α to mimic inflammation. NLRP12 knockdown was performed via lentiviral transduction. PANoptosis was assessed by Western blot (cleaved-Caspase-1, cleaved-Caspase-3, p-MLKL, c-GSDMD), TUNEL staining, and flow cytometry. In vivo, a rat IVDD model was induced by acupuncture puncture, followed by TLR4 knockdown via lentiviral injection. X-ray imaging was used to assess intervertebral space height, histology to evaluate disc morphology, and TUNEL assay to detect annulus fibrosus cell death.
Results: scRNA-seq revealed an increased abundance of Fibro-AFCs and Adh-AFCs in IVDD, alongside enrichment of cell death-related pathways. PANoptosis-related gene expression and cell death scores were elevated in degenerative samples. In vitro, TLR4 activation induced PANoptosis in AFCs, which was attenuated by either TLR4 inhibition or NLRP12 knockdown. Formation of the PANoptosome complex-characterized by colocalization of Caspase-8, ASC, and RIPK3-was observed in degenerative AFCs. In vivo, TLR4 silencing ameliorated IVDD pathology, as evidenced by improved disc height, and reduced cell death. To our knowledge, this is the first study to identify the occurrence of PANoptosis in AFCs.
Conclusion: TLR4 promotes PANoptosis in AFCs through NLRP12 activation, driving IVDD pathogenesis. The TLR4-NLRP12-PANoptosis presents a potential therapeutic target for IVDD.
Keywords: TLR4, NLRP12, PANoptosis, annulus fibrosus cells, intervertebral disc degeneration, inflammatory microenvironment, single-cell RNA sequencing
1Department of Orthopedics, Qinghai Provincial People’s Hospital, Xining, Qinghai, People’s Republic of China; 2Department of Orthopedics, The Second Affiliated Hospital of Army Medical University, Chongqing, People’s Republic of China; 3Department of Laboratory, Chongqing Xiqu Hospital, Chongqing, People’s Republic of China; 4Department of Gastroenterology, People’s Hospital of Anguo, Baoding, Hebei, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Chenhao Liu, Department of Orthopedics, Qinghai Provincial People’s Hospital, Xining, Qinghai, 810007, People’s Republic of China, Email juggmore@163.com Yu Zhai, Department of Orthopedics, The Second Affiliated Hospital of Army Medical University, Chongqing, 400038, People’s Republic of China, Email zhaiyu9501@tmmu.edu.cn
Purpose: Intervertebral disc degeneration (IVDD), a common degenerative disorder, is characterized by chronic inflammation and progressive cell death. PANoptosis, an integrated form of programmed cell death that merges pyroptosis, apoptosis, and necroptosis, has recently emerged as a key contributor to degenerative diseases. Although Toll-like receptor 4 (TLR4) and NLRP12 are known to regulate inflammatory signaling and cell death, their roles in mediating annulus fibrosus cells (AFCs). This study investigated how the TLR4–NLRP12 axis regulates AFC PANoptosis and contributes to IVDD progression.
Methods: Single-cell RNA sequencing (scRNA-seq) profiled cell heterogeneity and PANoptosis-related signaling in healthy/degenerative annulus fibrosus (AF) tissues. An in vitro IVDD model was established by treating AFCs with TNF-α to mimic inflammation. NLRP12 knockdown was performed via lentiviral transduction. PANoptosis was assessed by Western blot (cleaved-Caspase-1, cleaved-Caspase-3, p-MLKL, c-GSDMD), TUNEL staining, and flow cytometry. In vivo, a rat IVDD model was induced by acupuncture puncture, followed by TLR4 knockdown via lentiviral injection. X-ray imaging was used to assess intervertebral space height, histology to evaluate disc morphology, and TUNEL assay to detect annulus fibrosus cell death.
Results: scRNA-seq revealed an increased abundance of Fibro-AFCs and Adh-AFCs in IVDD, alongside enrichment of cell death-related pathways. PANoptosis-related gene expression and cell death scores were elevated in degenerative samples. In vitro, TLR4 activation induced PANoptosis in AFCs, which was attenuated by either TLR4 inhibition or NLRP12 knockdown. Formation of the PANoptosome complex-characterized by colocalization of Caspase-8, ASC, and RIPK3-was observed in degenerative AFCs. In vivo, TLR4 silencing ameliorated IVDD pathology, as evidenced by improved disc height, and reduced cell death. To our knowledge, this is the first study to identify the occurrence of PANoptosis in AFCs.
Conclusion: TLR4 promotes PANoptosis in AFCs through NLRP12 activation, driving IVDD pathogenesis. The TLR4-NLRP12-PANoptosis presents a potential therapeutic target for IVDD.
Keywords: TLR4, NLRP12, PANoptosis, annulus fibrosus cells, intervertebral disc degeneration, inflammatory microenvironment, single-cell RNA sequencing