Cellular and Molecular Biology

A systematic review of the toxicity of salsolinol and its metabolites

Jasmine Kaur Sidhu — 2025-12-28

Salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline) is a tetrahydroisoquinoline compound formed by the condensation reaction between dopamine and acetaldehyde. While it plays a role in normal physiological functions at physiological levels, elevated concentrations have been associated with toxicity. This study aimed to investigate the mechanisms underlying salsolinol toxicity. A literature search was conducted using PubMed and Scopus databases covering the years 2013 to 2023. A total of 6,678 studies were identified using predefined keywords such as "salsolinol," "tetrahydroisoquinoline," "DMDHIQ+," "N-methyl salsolinol," "toxicity," "toxic," and "toxin." Based on predetermined inclusion and exclusion criteria, 6,381 articles were excluded. Seven articles met the eligibility criteria and were critically appraised; all were included in this review. Most of the studies reviewed found that elevated levels of salsolinol in the blood and brain contributed to addiction-like behaviours, particularly in alcoholism, through enhanced dopaminergic signalling in the ventral tegmental area. Two studies examined the oxidative stress effects of salsolinol and its metabolites on neurons and their potential role in cancer development. A novel finding also implicated salsolinol in the degeneration of myenteric neurons, leading to alterations in gut function. Salsolinol and its metabolites exhibit toxic effects in both the central and peripheral nervous systems, primarily through oxidative stress and the modulation of addiction-related pathways. These findings underscore the need for further research to explore potential therapeutic targets to mitigate these pathological effects.

Modulatory effects of Mentha longifolia and Mentha spicata essential oils on Candida albicans biofilm formation

Ayshah Alrashidi — 2025-12-28

Mentha longifolia (horsemint) and Mentha spicata (spearmint) are economically valuable aromatic plants widely utilized in food, cosmetic, and pharmaceutical industries due to their rich reservoir of bioactive compounds. This study investigated the antifungal and antibiofilm properties of essential oils extracted from these species against various Candida strains, particularly Candida albicans, a major opportunistic pathogen responsible for oral and systemic infections. Essential oils were extracted via hydrodistillation using a Clevenger apparatus and chemically characterized through GC-MS, revealing that M. longifolia oil was predominantly composed of pulegone (29.7%), menthone (26%), and eucalyptol (17.8%), while M. spicata oil was mainly enriched in pulegone (68.5%), eucalyptol (5.2%), and thymol (3.5%). The antifungal activity, evaluated by agar-well diffusion and broth microdilution assays, showed inhibition zones ranging from 9–14 mm for M. longifolia and 9–12 mm for M. spicata, with corresponding minimal inhibitory concentrations (MICs) of 0.39–6.25 mg/mL and fungicidal concentrations (MFCs) of 12.5–100 mg/mL. Both oils markedly reduced biofilm biomass in a concentration-dependent manner, with up to 90% inhibition observed at 4× MIC. The potent biofilm disruption was attributed to the high terpenoid content, capable of altering fungal membrane integrity. Overall, these findings demonstrate that the essential oils of M. longifolia and M. spicata possess significant antifungal and antibiofilm potential, highlighting their possible application as natural, plant-derived therapeutic agents for controlling Candida-associated oral and biomedical infections.

Piezo1-mediated cellular apoptosis in breast cancer cells triggered by ultrasound and microbubbles

Nina Qu — 2025-12-28

Piezo1 ion channels play a crucial role in apoptosis regulation in human breast cancer cells (MCF-7), and this study evaluates the effects of Piezo1 agonist (Yoda1), inhibitor (GsMTx4), and ultrasound microbubble (USMB) treatment on cellular apoptosis pathways. In this research, in vitro cultures of normal breast epithelial cells (MCF-10A) and cancer cell lines (MCF-7, MDA-MB-231) were analyzed by Western blotting to determine Piezo1 protein levels, with MCF-7 selected for further analysis. Groups included control (untreated), Yoda1, USMB, GsMTx4, and USMB+GsMTx4, and apoptosis rates were measured via flow cytometry. Levels of apoptosis-related proteins (Bcl-2, Bax), endoplasmic reticulum stress proteins (GRP-78, Caspase 12), and mitochondrial pathway proteins (Cyt-c, Caspase 3, Caspase 9) were quantified, while JC-1 and Ca2+ fluorescent probes were used to assess mitochondrial membrane potential and intracellular Ca2+ concentration. Results showed MCF-7 cells expressed the highest Piezo1 levels. Yoda1 and USMB both markedly increased apoptosis, enhanced ER stress, and induced the mitochondrial apoptosis pathway in comparison to control, while GsMTx4 had the opposite effect and USMB reversed GsMTx4’s phenotype. The USMB group exhibited the lowest mitochondrial membrane potential and the highest Ca2+ fluorescence intensity. These findings indicate that USMB activates ER stress via Piezo1, induces mitochondrial dysfunction, elevates intracellular Ca2+, and thereby promotes apoptosis in breast cancer cells.

Whole-grain millets attenuate atherosclerosis by modulating cholesterol metabolism and the FGF-2/PI3K/Akt and Wnt-1/β-catenin pathways in high-cholesterol-fed rats

Haritha Rajan — 2025-12-28

Millets, rich in nutrients, have the potential to enhance immunity and combat diseases, including atherosclerosis. As a chronic inflammatory disease contributing to high global mortality, atherosclerosis involves key signaling pathways such as Reverse Cholesterol Transport, FGF-2, and Wnt-1/β-catenin. Hence, this study investigated the anti-atherogenic effects of wholegrain millets on these pathways in high-cholesterol-fed rats, highlighting their potential as plant-based therapeutic alternatives to current treatments with adverse effects. Serum lipid profile, atherogenic index, tissue cholesterol levels, activity of lipogenic enzymes, hepatic 3-hydroxy-3-methylglutaryl-CoA reductase, plasma lecithin cholesterol acyl transferase, cardiac and inflammatory markers, gene expression of key lipid metabolism and FGF-2-Wnt-1 pathway genes by RT PCR and qPCR. Protein levels of the FGF-2-Wnt-1 pathway by ELISA and histopathological and Oil-red-O analysis were evaluated. 10% millet intervention significantly improved lipid metabolism by normalizing lipid profiles, reducing atherogenic index, lowering tissue cholesterol and lipogenic enzyme activities, enhancing LCAT activity, upregulating ABCA1 and Apo A1, and downregulating Apo B in HCD-fed rats. Among the millets, Little Millet (LM) showed the most potent effect, significantly reducing cardiac markers (CK-MB, LDH, CRP), downregulating FGF-2/PI3K/Akt and Wnt-1/β-catenin signaling by upregulating GSK3β, and improving aortic structure with no lipid accumulation as shown by Oil-red O staining. Our study suggests that whole-grain millet consumption can effectively reduce atherosclerosis progression. Specifically, LM shows strong potential as a natural intervention for managing atherosclerosis through its regulatory effects on key signaling pathways.

Structure-based identification of liensinine as a natural allosteric SHP2 inhibitor with anti-proliferative activity in HepG2 cells

Beom Su Seo — 2025-12-28

SHP2, encoded by the PTPN11 gene, is a non-receptor tyrosine phosphatase that plays a key role in oncogenic Ras/MAPK signaling. Aberrant SHP2 activity contributes to the progression of various cancers, including liver cancer. In this study, we used an AI-based virtual screening platform (HyperLab) to evaluate 127 natural compounds for SHP2 allosteric inhibition. Liensinine, a bisbenzylisoquinoline alkaloid from Nelumbo nucifera, was identified as a top candidate with strong predicted binding to the SHP2 allosteric tunnel site. This tunnel-shaped pocket is located at the interface between the N-SH2, C-SH2, and PTP domains, where allosteric inhibitors stabilize SHP2 in its closed, inactive conformation by preventing domain rearrangement. Docking analyses using HyperLab and CB-Dock2 consistently supported its interaction with key regulatory residues. Biochemical assays confirmed that Liensinine inhibits SHP2 phosphatase activity in a dose-dependent manner, with an IC₅₀ of ~5.2 μM. In HepG2 cells, Liensinine reduced cell viability to approximately 70% at 20 μM and 50% at 50 μM, indicating a concentration-dependent cytotoxic effect. Additionally, RNA-seq data analysis revealed upregulated PTPN11 expression in hepatocellular carcinoma tissues compared to normal liver. These quantitative findings strengthen the experimental evidence for Liensinine’s inhibitory potential. Together, these findings suggest that Liensinine may serve as a natural SHP2 allosteric inhibitor with anticancer potential.

Characterization of COVID-19 patients in clinical, epidemiological, and laboratory settings: the role of vitamin D binding protein and vitamin D level in severity

Aleen Sardar Al-Noori — 2025-12-28

There are contradictory findings on the role of vitamin D-binding protein in COVID-19 development, disease severity, and outcomes. Therefore, we aimed to explore the association between the serum vitamin D level, DBP, and the COVID-19 severity and outcomes. In this cross-sectional study, we observed the suspected and confirmed admitted patients with COVID-19 for the possible outcomes after measurements of vitamin D, vitamin D binding protein (DBP). The study included patients with a mean age of 70.89 years (range: 28–99), mostly aged ≥60 years (84.81%) and male (54.43%). Most were admitted to medical wards (60.76%) or ICU (39.24%). The majority had confirmed COVID-19 (81.01%), while 12.66% were not diagnosed. Hospitalization duration varied: 1–3 days (21.52%), 4–7 (17.72%), 8–14 (37.97%), and >14 days (22.78%). Outcomes: 53.16% died, 34.18% discharged, 12.66% recovered. Disease severity was critical (41.77%), severe (30.38%), moderate (24.05%), and mild (3.80%). All received oxygen: 56.96% via reservoir mask, 36.71% continuous positive airway pressure (CPAP), and 6.33% nasal mask. Common comorbidities: hypertension (67.09%), diabetes (37.97%), ischemic heart disease (IHD) (25.32%), and smoking (21.52%). Symptoms: shortness of breath (77.22%), cough (75.95%), chest pain (60.76%). Fever types: persistent (44.59%) and high (27.03%). Only 25.32% were vaccinated (Pfizer 45%, AstraZeneca 30%, Sinopharm 25%), mostly with two doses (85%). Vitamin D was low (16.88). DBP protein (mean: 5.51, range: 0.15–25.20) showed no significant differences across outcomes or severity (p > 0.05). Our study's results, particularly the exceptionally low mean DBP value in a cohort with high COVID-19 severity and mortality, highlight a crucial area of investigation.

Curcumin-mediated synthesis of copper-doped TiO2 nanocomposite for potentially promising antioxidant, wound healing, and anti-apoptosis

Saja Zubair Dhabian — 2025-12-28

The paper provides a green, eco-friendly synthesis and analysis of a novel curcumin-based, copper-doped titanium dioxide nanocomposite (CuO/TiO₂ -Curcumin NC). Curcumin was also utilized as a green reducing agent and also capping agent thereby enhancing the biocompatibility and functional surface chemistry of the nanocomposite. Stability of the nanocomposite was established using various forms of analysis. The relative biological studies showed that the synthesized CuO/TiO₂ -Curcumin NC had a high antioxidant capacity compared to pure curcumin and ascorbic acid. It also exhibited a strong, dose-dependent cytotoxicity to the breast cancer cell line MDA-MB-231 that is aggressive. The nanocomposite caused remarkable tumor cell apoptosis which was mainly triggered by excess production of reactive oxygen species (ROS) that caused irreversible damage of mitochondria, and caspase-activation pathways. This nanocomposite showed a concentration-related ability to inhibit the migration and proliferation of cancer cells and thus highlighted its high anti-metastatic capacity. Besides, the copper -titanium nanocomposite (CuO/TiO₂-curcumin) had promising in vitro wound -healing effects. Taken together, the present results confirm the CuO/TiO₂ -curcumin nanocomposite to be a highly effective, multimodal therapeutic platform, and, therefore, holds a lot of potential in biomedical applications in the future, as an enhanced antioxidant, a powerful anticancer agent, and a scaffold to promote tissue repair and regenerative medicine.

Inhibition of the RIPK1-driven necroptotic pathway protects against hypotensive and tachycardic responses to LPS in a rat model of septic shock

Bahar Tunctan — 2025-12-28

Necroptosis, a lytic type of cell death that is dependent on RIPK1-activated RIPK3 and MLKL, has been implicated in the progression of septic shock-related events. However, the role of RIPK1/RIPK3/MLKL necrosome in hemodynamic alterations associated with necroptotic and inflammatory tissue injury due to bacterial infections has not been explored. Therefore, we aimed to investigate whether inhibition of the RIPK1-driven necroptosis by a selective inhibitor of RIPK1, Nec-1s, protects against hypotension and tachycardia associated with necroptotic-, inflammatory-, and injury-related changes induced by bacterial LPS in rats. We also investigated the effects of RIPK1 inhibition on TLR4/TRIF- and caspase-8-related pathways that may contribute to these changes induced by LPS. The MAP and HR values were recorded from the conscious animals using a tail-cuff method. Serum iNOS, HMGB1, MPO, and LDH levels were determined using ELISA kits. The immunoblotting method was used to determine the changes in the expression of proteins related to the TLR4/TRIF- and caspase-8-mediated necroptotic and inflammatory pathways in the TA, RA, PA, and MCA. In the heart, kidney, lung, and brain, histopathological changes were evaluated by the H&E staining method. Expression of RIPK1, RIPK3, MLKL, and HMGB1 proteins in these organs was determined using immunohistochemical staining. Nec-1s prevented LPS-induced hypotension and tachycardia, increased serum iNOS, HMGB1, MPO, and LDH levels as well as expression of unphosphorylated and/or phosphorylated proteins of TLR4/TRIF/RIPK1/RIPK3/MLKL/HMGB1-, TLR4/MyD88/TAK1/IKKβ/NF-kB/iNOS/NO/VASP-, and caspase-8-related pathways in the arterial vasculature, but did not increase RIPK1, RIPK3, and MLKL protein expression induced by LPS in the heart, kidney, and lung tissues. The LPS-induced increase in scores related to histopathological changes in the kidney was attenuated by Nec-1s. These findings suggest that inhibition of the RIPK1-driven necroptosis protects against hypotension and tachycardia, along with arterial and/or renal necroptotic-, inflammatory-, and injury-related changes during septic shock. It also seems that suppression of the TLR4/TRIF- and caspase-8-related pathways may contribute to the beneficial effects of Nec-1s during septic shock.

Multidimensional assessment of natural ligands fisetin, morin and rutin against factor XIIa activity using in vitro and in silico studies

Hassan A. Madkhali — 2025-12-28

The discovery of selective inhibitors of factor XIIa (FXIIa) is an attractive approach for development of new antithrombotics that do not interfere with normal hemostasis. Here we report an in vitro chromogenic assay and in silico molecular modeling-based integrated protocol for predicting the inhibitory aptitude of natural flavonoids, Fisetin, Morin, Rutin and the synthetic derivative (FXIIa-IN-4) of the FXIIa enzyme. The frontier molecular orbitals (FMO) analysis, accompanied by the electrostatic potential (ESP) maps and a non-covalent interaction (NCI) map, provided the information about electronic reactivity of the title compounds. Chromogenic assays data of assessed flavonoids, Fisetin, Morin and Rutin have been shown a dose-dependent inhibition of FXIIa activity, in which at higher concentration (1000 µM) they exhibited about 52.6%, 57.1% and 71.9% inhibition, respectively. Molecular docking studies showed that Rutin has the lowest binding energy with FXIIa (8.6 kcal/mol) and Fisetin has with optimal balance between affinity, structural compactness and reactivity. In addition, molecular dynamics enables comparison of the stability and flexibility of the various ligand–protein complexes. Fisetin is the ligand that provides best structural stability, and Rutin causes a greater conformational variation, but with more hydrogen bond interactions. A detailed absorption, distribution, metabolism, and excretion (ADMET) analysis revealed that FXIIa-IN-4 has the best ADMET profile, while Fisetin is the second. Morin and Rutin, on the other hand, were found to have less clear toxic effects. Taken together, although the in vitro chromogenic assessment results demonstrated that Rutin has superiority in inhibition of FXIIa enzyme activity, the overall obtained data indicated the importance of Fisetin among all tested flavonoid compounds as an equilibrative natural inhibitor demanding in vivo experimental confirmation and focused molecular modification.

The role of an immunohistochemical panel including CD45, CK5/6, and ER in classifying challenging breast lesions in Iraqi pathology

Saman Rafeeq Abdullah — 2025-12-28

Accurate diagnosis of breast lesions is often complicated by the morphological overlap between benign, pre-malignant, and malignant entities on hematoxylin and eosin (H&E) stained sections. This study evaluated the diagnostic utility of an immunohistochemical (IHC) panel, comprising Estrogen Receptor (ER), Cytokeratin 5/6 (CK5/6), and Leukocyte Common Antigen (CD45), in resolving these diagnostic ambiguities among Iraqi patients. The panel was designed to differentiate epithelial (ER, CK5/6) and lymphoid (CD45) lineages, enabling the distinction between benign, pre-malignant, and malignant processes. A retrospective cross-sectional analysis was performed on 120 challenging breast lesions where the initial H&E diagnosis was inconclusive. Statistical performance was assessed using sensitivity, specificity, and accuracy metrics, with significance determined at p < 0.05. The IHC panel resulted in the reclassification of 53 cases (44.2%), with the highest reclassification in ADH (72.0%). The combined panel demonstrated 91.1% sensitivity, 93.3% specificity, and 92.5% accuracy (p < 0.001) for differentiating benign from malignant lesions. ER and CK5/6 were decisive in the majority of reclassified cases. In conclusion, the three-marker IHC panel (ER, CK5/6, and CD45) provides a statistically significant improvement in diagnostic accuracy and reliability in challenging breast lesions, reducing diagnostic uncertainty and supporting optimal patient management.

TMAO converts cytochrome c into a pro-apoptotic peroxidase by destabilizing the heme-Met80 ligation

Kuldeep Singh — 2025-12-28

Trimethylamine N-oxide (TMAO), a gut microbiota–derived metabolite, has been linked to cardiovascular, renal, and hepatic disorders, but its direct impact on mitochondrial apoptotic machinery remains unclear. Here, we show that TMAO binds cytochrome c (Cyt c), disrupting its structural integrity and converting it into an apoptotically competent species. Spectroscopic analyses revealed that TMAO destabilizes the heme–Met80 axial ligation, shifting Cyt c from its native hexacoordinate to a pentacoordinate state. This conformational change enhances peroxidase activity, exposes hydrophobic clusters, and perturbs the Trp microenvironment, marking Cyt c’s transition from electron carrier to pro-apoptotic catalyst. Absorption spectra further showed splitting of the native 530 nm band into peaks at 520 and 550 nm, consistent with heme reduction. These alterations facilitate Cyt c release from the mitochondrial membrane and engagement in intrinsic apoptosis. Given that TMAO accumulates at higher concentrations in tissues enriched with oxygen transporters, such as kidney and liver, our findings provide mechanistic insight into its role in organ-specific toxicity, including chronic kidney disease (CKD) and non-alcoholic fatty liver disease (NAFLD). This study establishes a direct molecular link between TMAO and mitochondrial apoptosis via Cyt c destabilization, suggesting that stabilizing Cyt c could represent a therapeutic strategy against TMAO-associated pathologies.

Activation of the Na/K-ATPase oxidant amplification loop by uremic toxins drives adipocyte dysfunction in vitro

Hari Vishal Lakhani — 2025-12-28

Oxidative stress is a major contributor to chronic kidney disease (CKD) progression. In experimental CKD, circulating uremic toxins (UTs) increase reactive oxygen species (ROS) production, triggering the Na/K-ATPase-ROS amplification loop (NKAL). Dysfunctional adipocytes, as seen in obesity, are a source of ROS and inflammatory cytokines, further exacerbating oxidative stress. We hypothesized that UT exposure activates this signaling pathway in adipocytes, leading to redox imbalance and phenotypic changes, and that the Na/K-ATPase antagonist pNaKtide can mitigate these effects. Murine 3T3-L1 preadipocytes were treated for 5 days with indoxyl sulfate (IS) (50, 100, 250 µM) or p-cresol (50, 100, 200 µM), with or without pNaKtide (0.7 µM), in adipogenic media. Adipogenesis was assessed by Oil Red O staining, superoxide levels by dihydroethidium fluorescence, and gene expression of adipogenic, inflammatory, and apoptotic markers by RT-PCR. In parallel, visceral fat from lean West Virginian donors was used to isolate mesenchymal stem cells (MSCs), which were differentiated into adipocytes and treated for 14 days with IS (25, 50, 100 µM) with or without pNaKtide (1 µM) for morphological and molecular analyses. UT treatment reduced adipogenesis and increased apoptotic and inflammatory markers in both 3T3-L1 and MSC-derived adipocytes, consistent with NKAL activation. Treatment with pNaKtide restores redox balance and improves cellular phenotype, both in in vitro models, though its effects on inflammatory and oxidative markers. Our data showed for the first time UT-induced activation of the NKAL as a driver of adipocyte dysfunction in vitro. Targeting this pathway with pNaKtide may represent a novel therapeutic approach to reduce oxidative stress-mediated metabolic disturbances in CKD.

Structural dynamics of PCSK9 loss-of-function variants: implications for LDL cholesterol regulation and cardiovascular risk

Mohammed Tarique — 2025-12-28

Cardiovascular disease (CVD) is a leading global cause of mortality, and understanding its underlying mechanisms is crucial for developing effective interventions. The liver-derived protein PCSK9 (proprotein convertase subtilisin/kexin-type-9) plays a vital role in regulating lipoprotein metabolism by binding to the low-density lipoprotein receptor (LDLR) and promoting its lysosomal degradation, ultimately reducing low-density lipoprotein (LDL) clearance. Loss-of-function (LOF) variants in PCSK9 are associated with decreased LDL cholesterol (LDL-C) levels, suggesting that these variants may contribute to a lower risk of cardiovascular events. Our computational analysis of PCSK9 LOF variants revealed significant alterations in stability, flexibility, and free energy compared to the native protein. Protein-protein docking studies of both wildtype and mutant PCSK9 with LDLR demonstrated variations in binding energy and interacting residues. Notably, while the binding cavity remained the same as that of the wildtype, all variants exhibited distinct binding interactions. Molecular dynamics simulations further highlighted increased flexibility and solvent exposure in the mutant protein complexes. These findings indicate that LOF variants in PCSK9 induce substantial structural changes, leading to a decreased affinity for LDLR binding.

Toll-like receptor 3 in hepatitis B and C: a determinant of infection

Abdoul Karim Ouattara — 2025-12-28

Toll-like receptor 3 (TLR3) is a key component of the innate immune system that recognizes viral double-stranded RNA (dsRNA) as well as endogenous RNA released from necrotic cells. Unlike other TLRs, TLR3 signals exclusively through the TIR-domain-containing adaptor inducing interferon-β (TRIF). This activation triggers downstream cascades that culminate in the translocation of IRF3 and NF-κB, inducing type I and type III interferons (IFNs) alongside interferon-stimulated genes (ISGs) and pro-inflammatory cytokines. These responses are essential for shaping antiviral immunity in hepatitis virus infections. In hepatitis B virus (HBV) infection, exogenous stimulation of TLR3 using synthetic agonists such as polyriboinosinic: polyribocytidylic acid [poly(I:C)] suppresses viral replication in experimental models and promotes interferon-dependent viral clearance, underscoring its therapeutic potential. In hepatitis C virus (HCV) infection, TLR3-mediated antiviral defenses are directly antagonized, most notably through cleavage or downregulation of TRIF by viral proteins, thereby impairing IFN induction and facilitating viral persistence. Furthermore, human genetic studies reveal that TLR3 polymorphisms, such as the non-synonymous rs3775290 (1377 C > T), are associated with differential susceptibility, chronicity, and progression of HBV and HCV infections. Collectively, the evidence highlights TLR3 as a central determinant of host-virus interactions in hepatitis, influencing viral clearance, persistence, and clinical outcomes, and as a promising target for novel therapeutic strategies. This review provides an updated overview of TLR3 expression and genetic variants in relation to HBV and HCV infection outcomes.

Chronic inflammation in the development of colorectal cancer: pathological model and therapeutic targets

Alexander Blagov — 2025-12-28

Colorectal cancer is very severe and a hard disease to treat because it is the second most deadly type of cancer in the world. The primary causes of mortality from colorectal cancer, which can be associated with a common and potentially fatal malignancy, are metastases to the liver and peritoneum. Colorectal cancer is fueled by chronic inflammation, which is caused by immune system molecules that launch a cascade of reactions that lead to the emergence of positive feedback to maintain the resulting inflammatory response. Pro-inflammatory cytokines, such as interleukins 1, 6, and 17 (IL-1, IL-6, IL-17), along with tumor necrosis factor-alpha (TNF-α), are released into tumor sites during immune cell infiltration by macrophages. These cytokines play a critical role in promoting tumor invasion, growth, and survival. To develop innovative approaches to immune response modulation against cancer, a thorough knowledge of these intricate molecular interactions is essential. These approaches may include both targeting cytokines and inflammatory factors, as well as transcription factors such as STAT3/6, (TNF)-α, which underlie the initiation of inflammation. This review will present current knowledge on the role of chronic inflammation in colorectal cancer development, present a model of chronic inflammation development, and propose therapeutic targets based on it. This work will allow researchers and physicians to take a new look at one of the aspects of colorectal cancer pathogenesis. The pathological model and potential therapeutic strategies described in this review can become the basis for finding new therapeutic targets and developing drugs for the treatment of colorectal cancer.