Curcumin and piperine as emerging modulators of cancer progression: molecular mechanisms, gut microbiota interactions, and therapeutic applications

Cancer continues to be a major contributor to global morbidity and mortality, highlighting the need for multitarget therapeutic approaches that can address tumor heterogeneity, therapeutic resistance, and disease recurrence. Curcumin, the primary polyphenol obtained from Curcuma longa, exerts wide-ranging anticancer effects by modulating multiple oncogenic pathways, including NF-κB, STAT3, PI3K/Akt/mTOR, Wnt/β-catenin, MAPK, and Hippo/YAP signaling. However, its movement into clinical use has been constrained by poor aqueous solubility, rapid metabolism, extensive first-pass elimination, and restricted systemic exposure after oral intake. Piperine, an alkaloid extracted from Piper nigrum and Piper longum, has inherent anticancer, anti-inflammatory, and chemosensitizing activities, and it has been extensively studied as a potential enhancer of curcumin pharmacokinetics. Still, the growing body of evidence shows that piperine’s impact on curcumin bioavailability is variable and depends on the formulation, and newer experimental work has raised doubts about the consistency and broad applicability of the pharmacokinetic enhancement described in earlier studies. This review critically integrates current evidence on the therapeutic promise of curcumin–piperine combinations for cancer prevention and treatment, separating experimentally validated results from hypothesized mechanisms. Experimental findings indicate that the combination restrains tumor growth through coordinated regulation of apoptosis, cell-cycle progression, inflammatory signaling, oxidative stress, and cancer stem cell maintenance across multiple malignancies, including colorectal, breast, hepatocellular, lung, glioblastoma, and hematological cancers. Emerging evidence also implies that curcumin and piperine may influence gut microbiota composition, microbial metabolite profiles, intestinal barrier function, and host immune responses, thereby offering an additional—though still developing—mechanistic route through which this combination could affect carcinogenesis and therapeutic responsiveness. Advances in nanotechnology-based delivery systems, such as emulsomes, polymeric nanoparticles, magnetic nanoparticles, and gold nanogels, have substantially improved drug stability, controlled release, intracellular delivery, and antitumor efficacy in preclinical models, providing promising options to mitigate pharmacological limitations. While the available evidence supports the curcumin–piperine combination as a credible multitarget adjunct for cancer prevention and therapy, most data come from in vitro and animal studies, whereas well-designed clinical studies are limited. Future research should emphasize standardized formulations, thorough pharmacokinetic assessment, biomarker-driven clinical trials, careful evaluation of potential drug–drug interactions, and mechanistic studies that clarify host–microbiota–tumor interactions to determine the exact clinical role of curcumin–piperine combinations in precision oncology.