TWEAK modulates the characteristics of periodontal ligament stem cells via the Fn14/NF‑κB pathway.

Tumor necrosis factor‑like weak inducer of apoptosis (TWEAK)/fibroblast growth factor‑inducible 14 (Fn14) signaling represents a critical regulatory axis in tissue repair and the inflammatory response. However, the impact of TWEAK on the characteristics of periodontal ligament stem cells (PDLSCs), which subsequently influence periodontal homeostasis, remains inadequately understood. To address this, PDLSCs were isolated from human periodontitis tissue and cultured to investigate the effects of TWEAK on PDLSC proliferation, migration and osteogenic differentiation using Cell Counting Kit‑8, TUNEL, Transwell and scratch assays, and alizarin red and alkaline phosphatase staining. Transcriptome sequencing and western blot analysis were used to explore the underlying molecular mechanisms. Additionally, the potential of targeting TWEAK in periodontitis treatment was evaluated using inflammatory PDLSCs (iPDLSCs) and a rat periodontitis model. The present study demonstrated that low levels (1, 5 and 20 ng/ml) of TWEAK enhanced the proliferation and osteogenic differentiation of PDLSCs, with 1 and 5 ng/ml further enhancing their ability to promote M2 macrophage polarization. By contrast, elevated levels (100 ng/ml) of TWEAK impaired PDLSC proliferation, migration and osteogenic potential, activated the RANKL/osteoprotegerin (OPG) system, and promoted the M1 polarization of macrophages induced by PDLSCs, with the Fn14/NF‑κB pathway serving a pivotal role in this regulatory process. The expression levels of TWEAK, Fn14 and NF‑κB were significantly higher in iPDLSCs than in healthy donor‑derived PDLSCs, and these iPDLSCs exhibited reduced proliferation, migration and osteogenic potential, along with increased RANKL/OPG activation and M1 macrophage polarization. In iPDLSCs, inhibition of the TWEAK/Fn14/NF‑κB pathway enhanced cell proliferation, migration and osteogenic differentiation potential, and reversed the activation of the RANKL/OPG system and macrophage M1 polarization induced by iPDLSCs. Furthermore, high TWEAK levels were shown to accelerate the progression of rat periodontitis, while inhibition of the TWEAK/Fn14 pathway mitigated periodontitis‑induced periodontal tissue destruction in rats. Collectively, the present findings revealed the role of the TWEAK‑PDLSCs axis in the maintenance and disruption of periodontal homeostasis, and identified targeting of the TWEAK/Fn14/NF‑κB pathway in iPDLSCs during periodontitis as a promising therapeutic strategy.