Background: Nasopharyngeal carcinoma (NPC) is a highly metastatic epithelial malignancy with limited therapeutic options for advanced disease. Timosaponin AIII (TSAIII), a natural steroidal saponin, exhibits antitumor activity; however, its effects on NPC progression and the molecular mechanisms remain unclear. Method: Cell viability, proliferation, apoptosis, migration, and invasion were evaluated using cell growth, colony formation, Annexin V/PI, and Transwell assays. Human chemokine array and The Cancer Genome Atlas (TCGA) analyses identified midkine (MDK) as a potential molecular target of TSAIII and its clinical relevance in NPC. Western blotting, qRT-PCR, immunofluorescence, and chromatin immunoprecipitation (ChIP) assays were used to investigate the underlying signaling mechanisms. Antimetastatic activity was further evaluated in C.B17-SCID mice. Results: TSAIII suppressed NPC cell migration and invasion with minimal cytotoxicity, accompanied by reduced the expression of p-AKT (Ser473), estrogen receptor β(ERβ) nuclear localization, and MDK expression. Wortmannin enhanced these effects, while TSAIII attenuated latent membrane protein 1 (LMP1)-induced signaling. In vivo, TSAIII significantly reduced lung metastasis without apparent toxicity. Conclusions: TSAIII suppresses NPC metastasis by targeting the LMP1/p-AKT/ERβ/MDK signaling axis, supporting its potential as an antimetastatic therapeutic candidate for NPC.

Background/Objectives: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic inflammatory bladder disorder that lacks an effective treatment agent. Fucoidan (FUC), isolated from Fucus vesiculosus, is a sulfated polysaccharide that exhibits potent anti-inflammatory and anti-fibrotic activities. This study investigated the protective effects and underlying mechanisms of FUC in IC/BPS. Methods: NLRP3 inflammasome activation and AKT signaling were evaluated by Western blotting, qRT-PCR, immunofluorescence, pharmacological inhibition, gene silencing, and overexpression. Molecular docking assessed potential FUC–protein interactions. In vivo mouse model evaluated the protective effects and toxicity of FUC. Results: In SV-HUC-1 cells, FUC significantly attenuated TNF-α-induced expression of NLRP3 and cleaved caspase-1 and c-IL-1β expression at both the transcriptional and protein levels. Residual inflammasome activity after FUC treatment remained further suppressible by MCC950 or siNLRP3. FUC also reduced TNFα-induced AKT phosphorylation, whereas AKT silencing and overexpression enhanced and partially reversed the inhibitory effect of FUC on inflammasome signaling, respectively. The molecular docking results suggested potential interactions between FUC and key inflammasome-related proteins, including NLRP3, caspase-1, IL-1β, and AKT. In interstitial cystitis mice, FUC mitigated cyclophosphamide (CYP)-induced bladder injury, reduced bladder expression of inflammasome-associated markers, and exhibited no significant toxicity in major organs. Conclusions: These findings indicate that FUC alleviates urothelial inflammatory injury and experimental cystitis, at least in part, by suppressing the AKT/NLRP3 inflammasome axis, supporting its potential as a therapeutic candidate for IC/BPS.