Inflammation is a complex biological response initiated by diverse stimuli, including pathogens, tissue damage, and cellular stress. In response to these stimuli, immune and other cells produce a diverse group of molecules known as inflammatory mediators, including cytokines, chemokines, prostaglandins, and leukotrienes (46). While inflammation and inflammatory mediators are essential for the immune response and play a role in fighting infections and promoting tissue repair, excessive or chronic inflammation may develop various diseases, such as autoimmune disorders, metabolic disorders, and cancer (47–49). Therefore, modulation of inflammatory mediators has the potential to be a promising strategy for preventing and treating these conditions.

The efficacy of CUR in modulating the inflammatory response can be attributed to its capability to regulate multiple signaling pathways and molecules involved in inflammation. Numerous studies have demonstrated that CUR exerts anti-inflammatory effects by inhibiting the activity of several pro-inflammatory mediators, including cytokines (e.g., TNF-α, IL-1β, IL-6), chemokines (e.g., CXCL8, CCL2), and enzymes (e.g., COX-2, iNOS) (50, 51). The regulation of the inflammatory response by CUR is attributed to its ability to block the NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathway, which is vital in the inflammatory process (52). NF-κB, a ubiquitously present transcription factor, critically regulates the immune response, inflammation, cell proliferation, and apoptosis while participating in the expression of genes that regulate cellular responses to various stimuli, including stress, cytokines, free radicals, and microbial pathogens (53). In an inactive state, NF-κB is bound to inhibitor proteins, which prevent it from entering the nucleus and activating gene transcription. Upon activation, NF-κB translocates to the nucleus and activates the transcription of various pro-inflammatory genes. Moreover, CUR administration efficiently blocks the phosphorylation of the inhibitor of kappa B (IKK) and the inhibitor of NF-κB (IκB), which are necessary for the translocation of NF-κB into the nucleus in ulcerative colitis and cancer cells (54, 55). Furthermore, CUR also suppresses the activation of Toll-like receptors (TLRs) and downstream signaling pathways that lead to NF-κB activation (56). Overall, these findings indicate that CUR inhibits TLR activation and blocks the phosphorylation of IKK and IκB, subsequently preventing the translocation of NF-κB towards the nucleus. Ultimately, this cascade of events effectively inhibits the transcription of various pro-inflammatory genes.

The Activator Protein-1 (AP-1) pathway is an important pathway involved in CUR’s regulation of the inflammatory response (57). AP-1 is a transcription factor that promotes the transcription of several pro-inflammatory genes, such as cytokines, chemokines, and matrix metalloproteinases (MMPs) (58, 59). In line with this, Woo et al. revealed that CUR blocks AP-1 activation by inhibiting JNK, which phosphorylates and activates c-Jun (an AP-1 subunit) (60). Moreover, it has been demonstrated that CUR can directly bind to c-Jun and inhibit its DNA binding activity, thereby suppressing the expression of pro-inflammatory genes and alleviating inflammation (60). Furthermore, CUR can also depress the activity of inflammation-related enzymes (e.g., COX-2, iNOS) by inhibiting p38 MAPK signaling (61). Aside from its impact on inflammatory mediators, CUR has been observed to modulate the activity of immune cells involved in the inflammatory response, suppressing the production of pro-inflammatory cytokines TNF-α and IL-6 by macrophages and inducing the polarization of macrophages towards an anti-inflammatory M2 phenotype (62). These studies provide insights into the regulation of signaling pathways by CUR, which has been shown to inhibit the activation of NF-κB, AP-1, and MAPK, as well as the expression and activity of numerous pro-inflammatory mediators, underscoring its potential as a therapeutic agent for various inflammatory disorders.

Apoptosis, also referred to as programmed cell death, is a precisely regulated process that eliminates impaired or unneeded cells to maintain tissue homeostasis (63). Disruption of apoptosis can result in various pathological conditions, including autoimmune diseases, cancer, and neurodegeneration (11, 64, 65). Apoptosis is governed by an intricate network of signaling pathways, which include extrinsic and intrinsic pathways (66). The extrinsic pathway is triggered by the binding of extracellular ligands to death receptors (e.g., TNF, Fas receptors). In contrast, the intrinsic pathway is initiated by intracellular stress signals, such as oxidative stress and inflammatory response (67, 68). Therefore, comprehending the molecular mechanisms that regulate apoptosis and identifying effective strategies for modulating apoptosis is critical for preventing and treating diseases.

Compelling scientific and dietary evidence has demonstrated the potential of CUR to induce apoptosis in various cancer cells. For instance, CUR has been extensively investigated for its potential to inhibit the PI3K/AKT pathway in cancer cells, leading to the downregulation of downstream targets such as mTOR and inducing apoptosis (69, 70). The activation of the PI3K/AKT pathway, triggered by the production of 3’-phosphorylated phosphoinositides, is a critical signaling pathway involved in both apoptosis and cell cycle progression (71). Abnormal activation of the PI3K/AKT pathway hinders apoptosis by upregulating anti-apoptotic genes such as Bcl-2 and downregulating pro-apoptotic genes like Bax (71). In addition, CUR is validated to upregulate the expression of PTEN, a tumor suppressor that negatively regulates PI3K/AKT signaling, while downregulating the expression of genes involved in AKT activation (72). Moreover, CUR modulates upstream regulators of the PI3K/AKT/mTOR pathway, including growth factor receptors and integrins. Chiu et al. reported that CUR inhibits the activity of EGFR, a receptor tyrosine kinase that activates the PI3K/AKT pathway, leading to apoptosis induction in cancer cells (73). Aside from PI3K/AKT/mTOR pathway, the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is another major signaling pathway that regulates apoptosis (74). The JAK/STAT pathway is a signaling cascade that plays a critical role in the regulation of cell proliferation, differentiation, and apoptosis, and its dysregulation has been implicated in various diseases (74). In a myeloproliferative neoplasms model, CUR activates the JAK2/STAT pathway, inducing apoptosis and inhibiting proliferation, thus exerting an antitumor effect on human JAK2-mutated cells (75). Furthermore, it has been noted that CUR modulates several apoptotic pathways, including the death receptor and endoplasmic reticulum (ER) stress-induced apoptosis pathways (76). The death receptor pathway is initiated when death ligands, such as TNF and Fas ligand, bind to their respective receptors, activating caspase-8 and downstream effector caspases, ultimately leading to apoptosis (77). CUR has been shown to sensitize cancer cells to death receptor-mediated apoptosis by promoting Fas-receptor and by activation of caspase-3 and -8 in tumor cells (78). In addition, CUR activates the ER stress-induced apoptosis pathway, a critical membranous organelle during apoptosis, and participates in complex interaction with the mitochondria (79). Furthermore, in tumor therapy, CUR induces ER stress. It activates the unfolded protein response (UPR), leading to the upregulation of the pro-apoptotic proteins (CHOP and Bax) and the activation of caspase-3, which ultimately triggers apoptosis and exerts anti-tumor property (80). Experimental data have conclusively proved that CUR exerts anti-cancer effects by promoting apoptosis through several signaling pathways in cancer cells.

Intriguingly, CUR has also been demonstrated to possess inhibitory effects on apoptosis in non-cancerous diseases, expanding its potential therapeutic applications beyond cancer treatment. In diabetic cardiomyopathy, CUR inhibits apoptosis and alleviates oxidative stress by eliminating ROS levels and activating PI3K-AKT signaling pathways, resulting in the downregulation of caspase-3 and Bax protein expression (81). Moreover, CUR treatment was shown to attenuate apoptosis and inflammation by inhibiting JAK2/STAT3 and NF-κB signaling pathways, which results in the upregulation of Bcl-2, and the downregulation of Bax and caspase-3 in an acute kidney injury model (82). In addition, the treatment of CUR enhances the viability of Saos-2 cells, mitigates apoptosis, improves mitochondrial membrane function and potential, and upregulates the phosphorylation of GSK3b and protein kinase B (AKT) (83). Furthermore, in the gentamicin-induced nephrotoxicity model, CUR reverses the expression levels of ER stress markers (CHOP, calpain-2, caspase-12, and cleaved caspase-7) and decreased apoptotic protein biomarkers expression (cleaved caspase-3 and Bax) (84). Therefore, besides its anticancer effects through promoting apoptosis in cancer cells, CUR has also demonstrated the ability to inhibit apoptosis in non-cancerous diseases, such as diabetic cardiomyopathy and acute kidney injury. These significant findings underscore the multifaceted role of CUR in modulating apoptosis and establish a foundation for its therapeutic applications in diverse disease contexts.

Curcumin, a bioactive compound present in turmeric, has emerged as a potential health-promoting agent in the regulation of various diseases. This mini-review offers a comprehensive summary of recent advances in elucidating the preventive and curative effects of CUR on oxidative stress, inflammation, and apoptosis in non-cancerous diseases and cancers. Generally, CUR exhibits its antioxidant property through AMPK/Nrf2/ARE/Keap1 pathway activation, its anti-inflammatory property via NF-κB/AP-1/MAPK pathways inhibition, and its anti-apoptosis property by blocking JAK/STAT and ER stress-induced pathways while activating PI3K/AKT/mTOR pathways in non-cancerous diseases ( Figure 1 ). Conversely, CUR demonstrates pro-oxidant, anti-inflammatory, and pro-apoptosis properties in cancers ( Figure 1 ). Therefore, the future perspectives of CUR’s application encompass exploring novel drug formulations, investigating combination therapy approaches, conducting disease-specific clinical trials, developing targeted therapies, and integrating them with lifestyle interventions to optimize its therapeutic potential in both non-cancerous diseases and cancers. However, further research is necessary to comprehensively elucidate the underlying mechanisms of CUR in alleviating host diseases and to devise more effective clinical strategies.