This study provides a comprehensive evaluation of the therapeutic potential of fucoidan (FUC), a naturally occurring sulfated polysaccharide derived from brown seaweed (Fucus vesiculosus), against experimental infection with S. mansoni immature stages using parasitological, histopathological, and immunohistochemical approaches5. PZQ remains the mainstay of schistosomiasis treatment; however, its limited efficacy against juvenile schistosomula and concerns regarding reduced effectiveness in high-transmission settings underscore the need for alternative or adjunctive therapies10,11. Fucoidan has attracted interest because of its antioxidant, immunomodulatory, and anti-inflammatory properties, which may be relevant to parasite control and attenuation of infection-related tissue damage5,6.
In the present study, FUC produced time-dependent therapeutic effects. Body and liver weights increased in the treated groups compared with the infected controls, suggesting partial recovery of nutritional status and hepatic condition despite ongoing infection.
Total adult worm burden was significantly reduced in all FUC-treated groups; however, PZQ achieved complete elimination of adult worms, confirming its superior adulticidal activity. These findings are consistent with previous reports showing that fucoidan can reduce worm burden in schistosomiasis through indirect immunomodulatory effects rather than direct parasiticidal activity alone. They also agree with Mohamed et al., who reported a reduction in total worm burden in both PZQ- and FUC-treated mice, with greater reduction in the PZQ group12. In agreement with our findings, Mohamed et al.9 revealed that the percentage of total worm burden reduction in the PZQ treated group was 73.8% and with the FUC treated group by a reduction rate of 58.9%, compared with the infected untreated mice group.
The reduction in worm burden observed with FUC may reflect, at least in part, its capacity to modulate oxidative stress and host inflammatory responses, as previously suggested for other parasitic systems such as Leishmania donovani13. Similar anti-parasitic effects have also been reported for other seaweed-derived compounds, including Dictyota, which reduced adult S. mansoni counts in culture14. Together, these data support the notion that FUC exerts a moderate but meaningful anti-schistosomal effect that is most evident when administered early after infection.
Hepatic egg burden was markedly reduced following treatment, with the strongest reduction observed in the PZQ group, followed by FUC35 and FUC42. Importantly, FUC42 was associated with the highest proportion of immature eggs, whereas FUC7, FUC21, and FUC35 retained higher proportions of mature viable eggs. These findings indicate that the effect of FUC depends on treatment timing and is not uniform across all stages of egg development. Instead, the data supports a stage-dependent response, with treatment at later infection stages producing greater changes in egg viability and burden15,16. This interpretation is consistent with Ibrahim et al.17, who reported altered egg viability patterns in S. mansoni after treatment with pentoxifylline and PZQ.
Because egg viability is closely linked to granulomatous inflammation and transmission potential, these changes are biologically and clinically important. Previous work has suggested that the effect of FUC on egg production may also involve modulation of gut microbiota. Cortes et al. reported that S. mansoni infection reduces alpha diversity and depletes beneficial bacteria such as Lactobacillus18, whereas FUC may partially restore this dysbiosis by promoting Lactobacillus growth19. Because Lactobacillus has been associated with lower worm and egg burdens, this mechanism may contribute to the biological effects observed here20.
In addition, Mohamed et al.9 previously reported that FUC treatment at 60 dpi reduced worm burden, egg count, and immature ova, while increasing dead ova, supporting the broader anti-schistosomal potential of fucoidan.
Histopathological examination demonstrated pronounced timing-dependent differences in granuloma morphology and composition. Early FUC treatment (FUC7, FUC21, and FUC35) was associated with predominantly cellular granulomas, whereas infected controls, PZQ-treated mice, and FUC42-treated mice showed mainly fibrocellular granulomas. This shift toward a cellular pattern in the early treatment groups suggests that FUC may help limit progression toward more fibrogenic lesions21.
This pattern is consistent with the natural evolution of schistosomal granulomas, which initially contain predominantly inflammatory cells and later become more fibrotic as collagen deposition increases16.
It is also compatible with the idea that regulatory immune mechanisms emerge over time to restrain granuloma expansion. In this context, the benefit of early FUC administration may lie in preserving a less fibrogenic granuloma phenotype before chronic fibrotic remodeling becomes established22.
The granuloma stage data further support this interpretation, as FUC7, FUC21, and FUC35 predominantly exhibited stage 1 granulomas, whereas the infected control, PZQ, and FUC42 groups mainly showed stage 3 lesions. This stage distribution indicates that early FUC administration may prevent progression to advanced granulomatous stages characterized by extensive fibrosis and architectural disruption23.
This is further supported by the marked reduction in granuloma fibrosis in the early-to-mid treatment groups, which is particularly important because hepatic fibrosis is a major determinant of morbidity in chronic schistosomiasis24.
Inflammatory cell infiltration and focal necrosis around the central vein also showed a clear timing-dependent gradient. The infected controls exhibited marked inflammatory infiltration, whereas the PZQ and FUC42 groups showed moderate infiltration. In contrast, FUC7-treated mice displayed mild infiltration, and FUC21 and FUC35 groups showed minimal infiltration. These findings suggest that earlier FUC administration interrupts inflammatory cascades before more extensive tissue injury occurs25,26.
The reduction in granuloma size observed in FUC7, FUC21, and FUC35 further supports a morphometric benefit of early intervention, whereas PZQ and FUC42 produced only modest size reductions. Similar observations have been reported in S. japonicum infection, where FUC reduced granuloma size and fibrosis through suppression of pro-inflammatory signaling and enhancement of regulatory immune responses12.
The proportion of degenerated ova was significantly higher in FUC7, FUC21, and FUC35 groups than in the infected control, PZQ, and FUC42 groups. This suggests that early-to-mid FUC treatment may enhance egg degeneration by preserving an inflammatory environment capable of damaging entrapped ova before immune tolerance becomes dominant17,27. Since viable eggs continue to release immunostimulatory molecules that sustain granulomatous inflammation, increased egg degeneration is a biologically meaningful endpoint16.
Immunohistochemical analysis showed that FUC7, FUC21, and FUC35 significantly reduced hepatic TNF-α, IL-1β, and iNOS expression relative to the infected control, PZQ, and FUC42 groups. The weaker effect of FUC42 again supports a timing-dependent response. Reduced TNF-α expression may reflect suppression of NF-κB and MAPK-related inflammatory signaling, which has been described in multiple inflammatory models28,29,30. However, because TNF-α also contributes to granuloma formation and parasite control, these results should be interpreted as evidence of immunomodulation rather than simple anti-inflammatory suppression26.
Previous work by Mohamed et al.9 showed that combined FUC and PZQ treatment produced the greatest reduction in TGF-β expression compared with either monotherapy, supporting the relevance of this pro-fibrotic pathway in schistosomal pathology. Likewise, Abaza et al.31 documented significant immunomodulatory activity in experimentally infected S. mansoni mice, with decreased hepatic phosphorylated p65 and pro-inflammatory cytokines (IL-6, IL-12, and TNF-α), together with increased anti-inflammatory cytokines (IL-4 and IL-13) in FUC-treated groups.
IL-1β followed the same pattern as TNF-α. IL-1β is a key pro-inflammatory mediator that amplifies acute-phase responses and promotes cellular recruitment to granulomatous lesions26; therefore, its downregulation likely contributed to the reduced inflammatory pathology observed in this study. Fucoidan-mediated suppression of IL-1β may be mechanistically relevant because IL-1β is regulated by upstream inflammatory pathways, including NF-κB and MAPK signaling32,33.
Consistent with our findings, Bai et al.12 reported that FUC reduced hepatic inflammatory cytokine expression and phospho-p65 levels in S. japonicum-infected mice, supporting a similar anti-inflammatory mechanism in schistosomiasis.
iNOS expression also declined in the early-to-mid FUC groups. Although iNOS-derived nitric oxide can contribute to parasite killing, excessive production may promote oxidative stress and hepatocellular damage. Thus, the reduction observed here may reflect a more balanced host response, in which parasite control is maintained while tissue injury is limited. This interpretation is in line with previous reports that fucoidan can inhibit iNOS expression through NF-κB-related pathways in inflammatory settings33,34. In schistosomiasis, iNOS is induced primarily by inflammatory cytokines such as TNF-α and IL-1β, so the parallel reduction of these markers is biologically coherent35,36.
The present study has several important implications. First, it demonstrates that the therapeutic activity of fucoidan is strongly dependent on the timing of administration, with earlier treatment producing superior parasitological, histological, and immunohistochemical outcomes. Second, it suggests that FUC may be more useful as an adjunct or early-stage intervention than as a replacement for PZQ, which remains superior for complete adult worm elimination. Third, the data support a model in which fucoidan modulates host inflammatory and fibrotic responses rather than acting solely as a direct antiparasitic agent.At the same time, some limitations should be acknowledged. This study did not evaluate dose–response relationships, sex-related differences, or upstream signaling pathways such as NF-κB and TGF-β. In addition, the use of a single dose and a specific experimental model may limit generalizability. Further studies are warranted to determine the optimal combination regimen of PZQ and FUC and to explore its potential clinical relevance in acute schistosomiasis.