Inflammation-associated tissue injury is driven by complex interactions among inflammatory mediators, oxidative stress, and apoptosis, creating a need for therapeutic strategies capable of targeting multiple pathological processes. Plant-mediated zinc oxide nanoparticles (ZnO NPs) have attracted increasing interest because of their favorable biocompatibility and pharmacological potential. This study comprehensively evaluated the phytochemical composition, physicochemical characteristics, and anti-inflammatory efficacy of Frankenia hirsuta -derived biofunctionalized ZnO nanoparticles (FH-ZnONPs), while exploring potential molecular mechanisms using integrated computational analyses.

FH-ZnONPs were synthesized via a green approach and characterized by UV–Vis spectroscopy, FTIR, XRD, SEM, TEM, EDX, zeta potential, and dynamic light scattering (DLS). Phytochemical profiling and quantitative HPLC analysis confirmed the presence of phenolic constituents associated with nanoparticle surface functionalization. Anti-inflammatory and antinociceptive activities were evaluated using carrageenan-induced paw edema, acetic acid-induced writhing, formalin, and hot-plate models, together with histopathological, immunohistochemical, biochemical, network pharmacology, and molecular docking analyses.

FH-ZnONPs significantly attenuated inflammatory edema and nociceptive responses, reduced malondialdehyde (MDA) levels, restored endogenous antioxidant defenses (glutathione and catalase), decreased tissue TNF-α and COX-2 expression, preserved BCL-2 expression, and markedly improved histopathological features of inflammation-associated tissue injury. Network pharmacology predicted TNF, PTGS2, AKT1, MAPK1, MAPK3, and BCL2 as potential hub targets, while pathway enrichment analysis suggested possible involvement of PI3K–Akt, MAPK, TNF, apoptosis, and oxidative stress-related signaling pathways. Molecular docking provided supportive computational evidence for potential interactions between major phytochemical constituents and inflammation-associated proteins.

Collectively, these findings demonstrate that FH-ZnONPs possess significant anti-inflammatory and antinociceptive activity in experimental models of acute inflammation. The integrated computational analyses provide biologically plausible, hypothesis-generating evidence that is consistent with the observed pharmacological effects but does not establish direct molecular mechanisms. Further comparative and molecular validation studies are warranted to define the individual contribution of nanoparticle biofunctionalization and to experimentally verify the predicted signaling pathways.