Ibuprofen

Ibuprofen can be redefined as a multi-target drug, with the new function of reprogramming alternative splicing in cancer. Ibuprofen can activate multiple pro-apoptotic pathways—including PPAR-γ activation, p75NTR mRNA stabilization via p38-MAPK, death receptor 5 upregulation, β-catenin nuclear export, and NF-κB inhibition—collectively sensitizing tumor cells to apoptosis induced by TRAIL or chemotherapy. Distinct from other anti-inflammatory medicines, ibuprofen depletes the oncogenic RAC1b splice variant by translocating the SRPK1 kinase out of the nucleus, leading to decreased phosphorylation of the splicing factor SRSF1, and also repressing the β-catenin/TCF4-mediated transcription of SRSF3. The two-level regulation results in coordinated downregulation of proliferation and upregulation of apoptosis. The group suggests that tumors with particular molecular characteristics may be more sensitive to the splice-modifying action of ibuprofen.

Fig. 1 Ibuprofen modulates alternative splicing via cyclooxygenase-independent pathways. (Jordan P.; et al. 2019)

Li et al. developed an injectable, photocurable hydrogel that provided sustained release of ibuprofen (IBU) to treat infected diabetic ulcers. First, they synthesized amino-modified β-cyclodextrin whose hydrophobic cavity hosts IBU, overcoming its poor water solubility and short half-life. This inclusion complex was entrapped in a triple-cross-linked network: oxidised alginate (OSA) ionically gelled with Ca²⁺, covalently reacted with gelatin-methacryloyl (GelMA) via Schiff bases, and UV-photopolymerised to give an injectable paste that sets within seconds under 405 nm light.
The composite was non-cytotoxic in vitro: extracts polarised RAW264.7 macrophages to the anti-inflammatory M2 phenotype and down-regulated M1 macrophage markers. M2 macrophage conditioned media promoted endothelial tube formation and accelerated closure of L929 fibroblast scratches. This study shows that local, low-dose IBU delivery through this tunable composite represses chronic inflammation, while simultaneously supporting angiogenesis and matrix remodelling to provide a clinically translatable approach for diabetic ulcer treatment without systemic NSAID side-effects.

Fig. 2 Synthesis and application of the Ibuprofen-loaded composite hydrogel system. (Li Z.; et al. 2025)