Background/Objectives: Colorectal cancer (CRC) remains a major global health burden, marked by complex tumor–microenvironment interactions, genetic heterogeneity, and varied treatment responses. Effective preclinical models are essential for dissecting CRC biology and guiding personalized therapeutic strategies. This review aims to critically evaluate current experimental CRC models, assessing their translational relevance, limitations, and potential for integration into precision oncology. Methods: A systematic literature search was conducted across PubMed, Scopus, and Web of Science, focusing on studies employing defined in vitro, in vivo, and emerging integrative CRC models. Studies were included based on experimental rigor and relevance to therapeutic or mechanistic investigation. Models were compared based on molecular fidelity, tumorigenic capacity, immune interactions, and predictive utility. Results: CRC models were classified into in vitro (2D cell lines, spheroids, patient-derived organoids), in vivo (murine, zebrafish, porcine, canine), and integrative platforms (tumor-on-chip systems, humanized mice, AI-augmented simulations). Traditional models offer accessibility and mechanistic insight, while advanced systems better mimic human tumor complexity, immune landscapes, and treatment response. Tumor-on-chip and AI-driven models show promise in simulating dynamic tumor behavior and predicting clinical outcomes. Cross-platform integration enhances translational validity and enables iterative model refinement. Conclusions: Strategic deployment of complementary CRC models is critical for advancing translational research. This review provides a roadmap for aligning model capabilities with specific research goals, advocating for integrated, patient-relevant systems to improve therapeutic development. Enhancing model fidelity and interoperability is key to accelerating the bench-to-bedside translation in colorectal cancer care.

Background: Chronic inflammation drives colorectal cancer (CRC) progression, with PAR-2, a G-protein coupled receptor, linking extracellular inflammatory signals to tumor-promoting pathways via ERK1/2 phosphorylation, calcium mobilization, TNF-α upregulation, and apoptosis suppression. While curcumin has notable anti-inflammatory and anti-cancer properties, its effects on PAR-2 signaling in inflammation-driven CRC remain underexplored. Objective: This study investigates how curcumin modulates PAR-2 expression and downstream oncogenic signaling in inflammation-driven CRC cells and explores its potential direct interaction with PAR-2 at the structural level. Methods: HT 29 and Caco-2 CRC cell lines were exposed to lipopolysaccharide (LPS) to induce an inflammatory phenotype, followed by treatment with curcumin at 50 µM and 100 µM. PAR-2 and PAR-1 expression, along with downstream markers including ERK1/2, p-ERK, TNF-α, caspase-8, cleaved caspase-8, caspase-3, Bcl 2, and Bax, were analyzed by Western blot and quantitative PCR. Calcium mobilization was assessed using Fluo-4 dye-based fluorescence imaging. Apoptosis was quantified using MTT viability assays, AO/EtBr dual staining, and Annexin V/PI flow cytometry. In parallel, AlphaFold-predicted structural models of PAR-2 were used to perform molecular docking with curcumin using CB-Dock2, to identify potential binding pockets and assess binding energetics. Results: Curcumin selectively downregulated PAR-2—but not PAR-1—at both transcript and protein levels in a dose-dependent manner. This downregulation was accompanied by suppression of ERK phosphorylation and calcium signaling, inhibition of TNF-α secretion, and reversal of the anti-apoptotic signaling axis (Bcl 2 downregulation and Bax and caspase-3/-8 upregulation). Functional assays confirmed enhanced apoptosis in curcumin-treated cells. Computational docking revealed a high-affinity binding interaction between curcumin and the transmembrane domain of PAR-2, supporting the hypothesis of direct G-Protein-Coupled Receptor (GPCR) modulation. Conclusions: Our findings reveal that curcumin targets the PAR-2/ERK/TNF-α axis and reactivates apoptotic pathways in inflammation-driven CRC, establishing it as a potent, mechanistically validated candidate for therapeutic repurposing in CRC.