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. 2026 Jan 6;90:103993. doi: 10.1016/j.redox.2025.103993

Prenylterphenyllin, a regulator of P53, inhibits colorectal cancer progression through oxidative stress and energy metabolism pathway

Yuhan Zhang a,b,c,1, Yueqing Han c,1, Songmao Li c,1, Ruimin Shan c,1, Ling Lin c, Zhengyu Gu c, Ruiyu wang c, Yun Chen a,c,⁎, Jiao Xiao b,⁎⁎, Fangmei An d,⁎⁎⁎, Chupeng Hu c,⁎⁎⁎⁎, Chunyan He e,⁎⁎⁎⁎⁎
PMCID: PMC12816865  PMID: 41518847

Abstract

Colorectal cancer (CRC) is one of the most prevalent and deadly cancers globally, with poor prognosis primarily due to metastasis and resistance to conventional therapies. This study evaluated the antitumor potential of prenylterphenyllin, a natural product derived from Aspergillus candidus. Prenylterphenyllin significantly reduced CRC cells viability and migration, while promoting apoptosis and cell-cycle arrest. Transcriptomic analysis showed activation of the p53 signaling pathway and inhibition of cell-cycle-related genes. Prenylterphenyllin also disrupted mitochondrial function and oxidative phosphorylation, increasing oxidative stress. In vivo, it suppressed tumor growth and lung metastasis without notable toxicity. These results highlight that prenylterphenyllin is a promising candidate for CRC therapy, capable of inhibiting tumor growth, migration, and metastasis while inducing apoptosis through the modulation of energy metabolism and oxidative stress. As a promising candidate, prenylterphenyllin may offer new therapeutic opportunities for CRC, particularly for metastatic disease. Collectively, this study identifies prenylterphenyllin as a novel therapeutic candidate for CRC and illuminates its promising therapeutic potential.

Keywords: Colorectal cancer, Prenylterphenyllin, Oxidative phosphorylation, ROS, Apoptosis

1. Introduction

CRC is a major contributor to global cancer mortality, ranking second in cancer-related deaths [1]. Treatment resistance and metastatic spread continue to limit prognosis, despite notable progress in early detection and therapy [[2], [3], [4], [5]]. Metastatic CRC is responsible for the majority of CRC-related fatalities, with poor survival rates mainly resulting from late-stage diagnosis and the disease's aggressive behavior [6,7]. Current treatments, including chemotherapy, are limited by significant side effects, drug resistance, and insufficient efficacy, highlighting the urgent need for novel therapeutic agents [5,[8], [9], [10]].

Malignant tumor cells exhibit energy metabolism reprogramming characteristics due to proliferation, differentiation, and stress responses [[11], [12], [13]]. Recent studies indicate a significant upregulation of mitochondrial OXPHOS-related gene expression in CRC [[14], [15], [16], [17], [18]]. Although glycolysis (the Warburg effect) dominates in certain tumors, both glycolysis and OXPHOS can coexist during the progression [12,19,20]. Notably, 5-fluorouracil resistance in CRC cells is linked to a metabolic shift from glycolysis to OXPHOS [14]. Additionally, drug-resistant CRC-derived cancer stem cells (CSCs) enhance oxidative metabolism by upregulating respiratory enzymes and oxygen utilization through the SIRT1 and PGC-1α signaling pathways [15].

Reactive oxygen species (ROS), the primary molecular mediators of oxidative stress, are well-established as pivotal drivers of tumor initiation, proliferation, and recurrence [[21], [22], [23]]. However, when ROS levels exceed a critical threshold, they inflict damage on mitochondrial and cellular structures, culminating in mitochondrial dysfunction [24]. This impairment disrupts the OXPHOS process, thereby attenuating ATP synthesis and affecting the cellular energy supply. Furthermore, excessive ROS accumulation triggers intracellular stress responses including activation of autophagy and apoptosis pathways, ultimately culminating in tumor cell death [[25], [26], [27]]. Therefore, while ROS play a dual role in promoting growth and adaptation to the tumor microenvironment, their excessive accumulation exerts a suppressive effect on OXPHOS and restricts tumor cell survival by inducing cell death. This dualistic behavior underscores the therapeutic potential of targeting ROS levels or OXPHOS pathways to selectively eliminate tumor cells.

Natural products represent a vast and invaluable source of novel therapeutic compounds, with bioactive substances derived from microorganisms, marine organisms, and botanical sources being particularly noteworthy for their pharmacological potential [28,29]. Prenylterphenyllin was first isolated from a solid substrate culture of Aspergillus candidus, and is a p-terphenyl derivative distinguished by its oxygen-containing functional groups and prenyl modifications [30,31]. While prior studies have demonstrated its measurable cytotoxic effects on various human cancer cell lines [30,32], its special effects on CRC and its underlying molecular mechanisms remain poorly understood. Given the urgent need for effective therapies against CRC, particularly those targeting both primary tumors and metastatic progression. Therefore, this study aimed to elucidate the therapeutic potential of prenylterphenyllin in CRC.

This study systematically investigates the effects of prenylterphenyllin on CRC cells, evaluating its impact on cell viability, migration, and metastasis, with a particular focus on its role in modulating cell cycle, apoptosis, and energy metabolism. Through comprehensive in vitro cell culture experiments and in vivo mouse models, we demonstrate prenylterphenyllin's efficacy in suppressing tumor growth and metastasis in CRC is investigated. Furthermore, we elucidate the molecular mechanisms underlying its anticancer activity. Collectively, our findings identify prenylterphenyllin as a promising therapeutic candidate for CRC intervention.

2. Materials and methods

2.1. Antibodies and reagents

Hoechst 33258 (C1017), Cell Counting Kit-8 (C0038), TMRE (C2001S), Mito-Tracker Green (C1435 M), MitoSO™ Red (S0061 M), Cell Cycle and Apoptosis Analysis Kit (C1052), and ROS Assay Kit with CM-H2DCFDA(S0035 M) were obtained from Beyotime. Apoptosis Kit (E-CK-A211) was purchased from the Elabscience. Oxaliplatin (HY-17371) was purchased from the MCE. Anti-β-actin (20536-1-AP), anti-Caspase3 (19677-1-AP), anti-Cleaved caspase3 (25128-1-AP), anti-Bax (50599-2-Ig), anti-Bad (10435-1-AP), anti-Bcl-2 (12789-1-AP), anti-E-cadherin (26874-1-AP), anti-P53 (10442-1-AP), anti-E-cadherin (20874-1-AP), anti-N-cadherin (22018-1-AP), anti-Vimentin (10366-1-AP), anti-Nrf2 (16396-1-AP), anti-Keap1 (10503-2-AP), anti-Nqo1 (11451-1-AP), and anti-Ho1 (10701-1-AP) were obtained from Proteintech. Anti-Ki67 (Ab15580) was purchased from Abcam.

2.2. Fungal material and fermentation

In this study, prenylterphenyllin was isolated from a marine-derived Aspergillus candidus SYPHU 492, isolated from a sponge collected from the Guangdong Province in China. The fermentation contains 140.0g rice, 4.4g sea salt, and 160 mL water, incubated at 26 °C for 30 days. After that, the mixture was extracted three times with EtOAc, and was then concentrated under reduced pressure to afford an EtOAc extract (160g). Using silica gel (200–300 mesh) column chromatography and CH2Cl2–MeOH(100:0–1:1, V:V) to yield seven fractions Fr.1–Fr.7. Fraction 4 (3 g) was further purified by silica gel (300–400 mesh) column chromatography to obtain Fraction 4-1. Fraction 4-1 (860 mg) was further separated by semi-preparative HPLC (75 % methanol in H2O, flow rate 3 mL/min) to obtain prenylterphenyllin.

2.3. Cell culture

Human CRC cell lines (SW480, SW620, HCT116) were obtained from Shanghai Zhong Qiao Xin Zhou Biotechnology Co., Ltd (Shanghai, China), and murine CRC cell lines (MC38, CT26) were purchased from Procell Life Science & Technology Co., Ltd (Wuhan, China). These cell lines were identified through Short Tandem Repeat (STR) profiling. All cell lines were grown at 37 °C in a 5 % CO2 incubator using DMEM supplemented with 10 % fetal bovine serum.

2.4. Cell viability assay

Cell viability was assessed using the CCK-8 assay. Cells were seeded into 96-well plates at a density of 5000 cells per well and allowed to attach for 12 h. They were then exposed to graded concentrations of prenylterphenyllin for 24 or 48 h. Following treatment, 10 μL of CCK-8 solution was added to each well and incubated for 1 h at 37 °C. Absorbance at 450 nm was subsequently measured to determine cell viability.

2.5. Wound healing assay

SW480, SW620, and HCT116 cells were seeded into 6-well plates and cultured under standard conditions until reaching approximately 90 % confluence. A linear wound was introduced into the monolayer using a 10 μL pipette tip. Detached cells were removed by rinsing with PBS, and the remaining adherent cells were incubated in fresh medium for 4 h. Subsequently, cells were exposed to various concentrations of prenylterphenyllin and cultured for 48 h. Wound closure was monitored under a microscope, and the wound width was quantitatively assessed using ImageJ software.

2.6. Cell cycle analysis

SW480, SW620, and HCT116 cells were treated with prenylterphenyllin for 24 h or 48 h, then collected by trypsin digestion, cleaned with PBS once, and fixed overnight at room temperature with 70 % ethanol. Fixed cells were collected by centrifugation and incubated at room temperature for 30 min in the dark in PI staining solution (50 μg/mL in PBS) and 0.1 mg/mL RNase A. Flow cytometric analysis was conducted using a BD FACSCalibur flow cytometer, with acquisition of 20,000 events per sample. Cell-cycle distribution profiles were subsequently analyzed using FlowJo software (version 10.8.1).

2.7. Apoptosis assay

Apoptosis was assessed using an Annexin V-FITC/PI double-staining assay. SW480, SW620, and HCT116 cells were treated with prenylterphenyllin for 24 or 48 h, then harvested by trypsinization and washed twice with pre-chilled PBS. The cells were resuspended in 1 × annexin binding buffer, and 100 μL of the cell suspension was incubated with 2.5 μL Annexin V-FITC and 2.5 μL PI for 15 min at room temperature in the dark. After adding 400 μL of 1 × annexin binding buffer, samples were immediately analyzed by flow cytometry. Cells positive for Annexin V (early apoptosis) and cells positive for both Annexin V and PI (late apoptosis) were considered apoptotic.

2.8. Western blot analysis

SW480, SW620, and HCT116 cells were treated with prenylterphenyllin for 24 h, then digested and centrifuged to collect the cells. Protein was extracted using RIPA lysis buffer. Protein samples (15–30 μg) were subjected to SDS-PAGE electrophoresis and transferred to PVDF membranes. Following incubation with 5 % skim milk powder reconstituted in phosphate-buffered saline with Tween-20 (PBST) at room temperature for 1 h, the membranes were incubated overnight at 4 °C with the corresponding primary antibody. The following day, the membranes were treated with the corresponding secondary antibody at room temperature for 1 h. Finally, protein signals were detected using a gel imaging system.

2.9. Immunofluorescence

After treatment with prenylterphenyllin for 24 h, the cells were washed twice with PBS. Then, 1 mL of TMRE working solution, DCFH-DA working solution, Mito-Tracker Green working solution, and MitoSO Red working solution, each containing DAPI, was added to the cells and thoroughly mixed. The cells were incubated incubator for 30 min in a humidified 5 % CO2 incubator at 37 °C. After incubation, the culture supernatant was discarded and the cells were washed twice with PBS prior to observation under an inverted fluorescence microscope.

2.10. RNA sequencing and differential gene enrichment analysis

HCT116 cells were incubated with 20 μM prenylterphenyllin for 24 h and then lysed with TRIzol Reagent to extract total RNA. RNA samples were assessed for quality on a NanoPhotometer® spectrophotometer and with the Agilent 2100 RNA Nano 6000 Assay Kit, followed by sequencing performed at Shanghai Personal Biotechnology Co., Ltd. (Shanghai, China). Gene differential expression analysis was conducted using DESeq2, and results were visualized using the R package. Functional annotation and integrated discovery were performed using information from the GO and KEGG pathway databases.

2.11. Animal experiments

Male BALB/c nude mice (5–6 weeks), male C57BL/6 mice (6–8 weeks), and male BALB/c mice (6–8 weeks) were purchased from the Animal Center of Nanjing Medical University and were raised under the guidance of the Ethics Committee of Nanjing Medical University (NQ: 1905048). Mice were housed under specific pathogen-free conditions with appropriate temperature and humidity control for one week prior to tumor implantation. HCT116 cells (5 × 106) were injected subcutaneously into BALB/c nude mice, while MC38 (1 × 106) and CT26 (1 × 106) cells were administered into C57BL/6 and BALB/c mice, respectively [[33], [34], [35], [36], [37]]. Animals were randomly allocated into four treatment groups, each containing 5–6 mice: control, oxaliplatin (5 mg/kg, administered twice weekly), prenylterphenyllin (10 mg/kg/day), and prenylterphenyllin (20 mg/kg/day). Tumor size was monitored every 2–3 days.

For the CRC lung metastasis experiment, HCT116, MC38, and CT26 cells (1 × 106/mL) were collected and injected (0.1 mL) into the tail vein of mice. After 24 h, the mice were treated with either no drug or with different doses of prenylterphenyllin (10 mg/kg and 20 mg/kg, once daily) or oxaliplatin (5 mg/kg, twice a week) via intraperitoneal injection for 30 days.

2.12. Statistical analysis

All data are expressed as mean ± SEM, and statistical analysis was performed using GraphPad Prism software 8.3.0. Comparisons between two groups were analyzed using Student's t-test. Multi-group comparisons were assessed using one-way analysis of variance (ANOVA). ∗p < 0.05, ∗∗p < 0.01 or ∗∗∗p < 0.001 were considered significant differences.

3. Results

3.1. Prenylterphenyllin exhibits cytotoxicity to colorectal cancer cells

The structure of prenylterphenyllin is presented in Fig. 1A. To assess its effects on CRC cell viability, CCK8 and crystal violet staining assays were performed on HCT116, SW620, and SW480 cells. As shown in Fig. 1B–D, prenylterphenyllin significantly decreased cell viability in a time- and dose-dependent manner compared with the control. The viability of HCT116, SW620 and SW480 cells after 24 h of treatment was 84.5 %, 99.6 % and 68.1 % with 5 μmol/L prenylterphenyllin, 81.8 %, 92.5 % and 56.2 % with 10 μmol/L prenylterphenyllin, 71.7 %, 79.2 % and 40.7 % with 20 μmol/L prenylterphenyllin, 35.5 %, 57.4 % and 37.7 % with 40 μmol/L prenylterphenyllin, 16.9 %, 22.8 % and 28.6 % with 80 μmol/L prenylterphenyllin, respectively. After treatment with prenylterphenyllin and subsequent crystal violet staining, the morphologies of live HCT116, SW620 and SW480 cells were analyzed. A time- and dose-dependent reduction in viable cell count was observed with escalating drug concentrations and prolonged exposure durations. The corresponding morphological changes were consistent with the quantified cell viability outcomes (Fig. 1E–M).

Fig. 1.

Fig. 1

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Prenylterphenyllin exhibits cytotoxicity to colorectal cancer cells. (A) Chemical structure of prenylterphenyllin. (B–D) Cell viability of HCT116, SW620, and SW480 cells. (E–G) Morphological alterations were assessed by live-cell microscopy. (H–M) Representative images and quantification of crystal violet-stained cells were shown after prenylterphenyllin treatment.

3.2. Prenylterphenyllin induces the differentially expressed genes

HCT116 cells were exposed to 20 μmol/L prenylterphenyllin to explore how this compound suppresses CRC cell proliferation and growth. RNA sequencing was then performed, including five replicates for both treatment and control groups. The results indicated that prenylterphenyllin alters the global gene expression profile, particularly affecting translational processes in HCT116 cells. As shown in Fig. 2A and B, a total of 3755 genes were differentially expressed following prenylterphenyllin treatment compared with the control group, including 1452 genes upregulated and 2303 genes downregulated. Since more genes were repressed than activated, it can be inferred that prenylterphenyllin exerts a strong inhibitory effect on gene transcription in HCT116 cells, leading to impaired cellular activity. Interestingly, we observed the upregulation of pro-apoptotic genes (DIABLO, BAX, BAD, and PPARP1) and the downregulation of anti-apoptotic genes (BIRC7, XIAP, BCL2, and ACTG1) following prenylterphenyllin treatment (Fig. 2C). To elucidate the biological functions of differentially expressed genes in prenylterphenyllin-treated HCT116 cells, pathway enrichment analysis was performed. GO enrichment revealed significant downregulation of pathways related to ribonucleoprotein complex biogenesis and regulation of cell cycle phase. Consistently, KEGG pathway enrichment analysis demonstrated marked activation of the p53 signaling pathway, accompanied by suppression of cell cycle-associated pathways. These findings collectively suggest that p53 serves as a pivotal mediator of prenylterphenyllin-induced apoptosis and cell cycle arrest (Fig. 2D–F).

Fig. 2.

Fig. 2

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RNA sequencing results of HCT116 cells treated with prenylterphenyllin. (A) PCA analysis of the RNA-seq data. (B) Volcano plot showing DEGs in HCT116 cells. (C) Expression profiles of apoptosis-related genes. (D–F) GO and KEGG enrichment analyses significant downregulation of cell cycle-related pathways and upregulation of the p53 signaling pathway.

3.3. Prenylterphenyllin promotes apoptosis and cell cycle arrest in CRC cells by enhancing p53 expression

As shown in Fig. 2F, GSEA enrichment analysis revealed that prenylterphenyllin treatment perturbed cell cycle progression, apoptosis, and the p53 signaling pathway in HCT116 cells. Given the pivotal role of the p53 signaling pathway in apoptosis and cell cycle regulation, we hypothesize that prenylterphenyllin may induce these effects through modulation of p53 activity. After 24 or 48 h prenylterphenyllin treatment, prenylterphenyllin significantly induced early and late apoptosis in HCT116, SW620, and SW480 cells compared to the control group (Fig. 3A–F). Interestingly, SW620 and SW480 cells, which harbor the R273H mutation in the p53 DNA-binding domain, also exhibited apoptotic responses similar to those observed in the wild-type p53 HCT116 cells. Upon prenylterphenyllin treatment, both mutant cell lines showed increased levels of pro-apoptotic proteins (Bax and Bad) and reduced levels of anti-apoptotic proteins Bcl-2, accompanied by an increase in p53 expression (Fig. 3G–I). Although the precise mechanism remains to be elucidated, these findings raise the possibility that prenylterphenyllin may partially modulate mutant p53 activity or influence p53-related pathways through alternative mechanisms [38,39], thereby promoting apoptosis and cell-cycle arrest even in mutant p53 background. This unexpected observation is particularly intriguing and may hold important scientific implications.

Fig. 3.

Fig. 3

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Prenylterphenyllin induces apoptosis in CRC cells. (A) Flow cytometry analysis of apoptosis in HCT 116 cells. (B) Statistical analysis of early cell apoptosis and late cell apoptosis rates. (C) Representative flow cytometry analysis of apoptosis in SW 620 cells. (D) Quantitative results of early cell apoptosis and late cell apoptosis rates. (E) Representative flow cytometry analysis of apoptosis in SW 480 cells. (F) Statistical analysis of early cell apoptosis and late cell apoptosis rates. (G–I) Western blot analysis of apoptosis-related proteins in HCT116, SW480, and SW620 cells.

Cell cycle progression was examined by flow cytometry. Upon prenylterphenyllin exposure, HCT116, SW620, and SW480 cells exhibited a higher proportion of S-phase cells and a concomitant decrease in the G1 population relative to the control group (Fig. 4A–D). Taken together, these findings demonstrate that prenylterphenyllin induces apoptosis and S-phase cell cycle arrest in HCT116, SW620, and SW480 cells, likely via p53-mediated regulation.

Fig. 4.

Fig. 4

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Prenylterphenyllin inhibits the migration ability of CRC cells. (A–C) Flow cytometry analysis of cell cycle distribution in HCT116, SW480, and SW620 cells prenylterphenyllin for 24 h. (D) Quantitative analysis of cell cycle phase distribution. (E–G) Representative wound-healing assays of cell migration in HCT116, SW480, and SW620 cells treatment with prenylterphenyllin. (H) Quantification of wound closure rate. (I–K) Western blot analysis of EMT-related proteins in HCT116, SW620 and SW480 cells after treatment.

3.4. Prenylterphenyllin inhibits the migration ability of CRC cells

The inhibitory effect of prenylterphenyllin on CRC cell migration was first examined using a scratch assay. In the control group, HCT116, SW620, and SW480 cells exhibited a strong migratory ability, with the scratch area nearly fully repopulated after 48 h. In contrast, prenylterphenyllin treatment significantly suppressed cell motility. Increasing concentrations of prenylterphenyllin led to a progressively larger residual scratch area, indicating dose-dependent inhibition of cellular migration (Fig. 4E–H). To further investigate the underlying mechanisms, we assessed the expression of metastasis and epithelial-mesenchymal transition (EMT)-related proteins by western blotting after treatment for 24 h. The results showed a clear upregulation of E-cadherin, an epithelial marker associated with reduced motility, and accompanied by a downregulation of the mesenchymal markers N-cadherin and Vimentin in all three CRC cell lines (Fig. 4I–K). Taken together, these in vitro findings demonstrate that prenylterphenyllin significantly suppresses the migratory potential of HCT116, SW620, and SW480 cells in a concentration-dependent manner, at least in part through the modulation of EMT-associated protein expression.

3.5. Prenylterphenyllin regulates energy metabolism

Metabolic reprogramming is a hallmark of cancer cells, enabling their rapid proliferation and survival under the nutrient- and oxygen-limited conditions characteristic in the tumor microenvironment [40,41]. Ye Yan et al. reported that PHB2 enhances mitochondrial function and oxidative phosphorylation in CRC, promoting CRC cell proliferation and tumorigenesis [42]. CRC cells also exhibit dysregulated mitochondrial activity, enhanced lipid biosynthesis, and altered amino acid utilization, collectively contributing to metabolic plasticity [43,44]. Given these features, prenylterphenyllin likely exerts its antitumor effects by disrupting metabolic adaptations through OXPHOS inhibition or glycolytic flux alteration, thereby disturbing energy homeostasis and imposing metabolic stress on tumor cells. Such perturbations are known to activate downstream signaling pathways, notably p53, which orchestrates cell cycle arrest and apoptosis in response to cellular stress. To further validate this hypothesis, we employed a targeted energy metabolomics. HCT116 cells were treated with 20 μmol/L prenylterphenyllin for 24 h underwent LC-MS/MS-based metabolite profiling, identifying 241 metabolites linked to key energy metabolic processes.

To characterize metabolic alterations, multivariate statistical analyses were performed. PCA revealed clear separation between control and treatment groups (Fig. 5A), while OPLS-DA further supported this distinction (Fig. 5B). Consistently, heatmap visualization and volcano plot analysis revealed substantial differences in metabolite abundance between the two groups (Fig. 5C and D). These results confirmed the reproducibility and quality of the samples, providing a reliable basis for downstream functional analysis. Subsequent KEGG pathway enrichment showed that differentially accumulated metabolites were predominantly associated with cancer-related pathways, including central carbon metabolism, OXPHOS, cofactor biosynthesis, pyrimidine metabolism, and the TCA cycle (Fig. 5E). Together, these findings suggest that prenylterphenyllin profoundly alters energy metabolism in CRC cells, thereby disrupting metabolic homeostasis and promoting tumor-suppressive responses.

Fig. 5.

Fig. 5

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Prenylterphenyllin regulates energy metabolism in HCT116 cells. (A) PCA analysis of the targeted energy metabolomics of control and prenylterphenyllin-treated groups. (B) OPLS-DA score plot demonstrating distinct metabolic profiles between control and prenylterphenyllin treated HCT116 cells. (C) Volcano plot displaying differentially expressed metabolite. (D) Heatmap showing expression patterns of differentially expressed metabolites between control and prenylterphenyllin-treated groups. (E) KEGG pathway enrichment analysis of control and prenylterphenyllin-treated groups.

3.6. Prenylterphenyllin induces oxidative stress via the Keap1/Nrf2/HO-1/NQO-1/pathway in CRC cells

Metabolomics analysis revealed that prenylterphenyllin inhibits OXPHOS in HCT116 cells. To elucidate the downstream cellular effects of OXPHOS inhibition, we conducted comprehensive analyses revealing a cascade of mitochondrial dysfunction. The suppression of OXPHOS impaired mitochondrial dysfunction, leading to increased ROS generation. In addition to a reduction in ATP synthesis, the suppression of OXPHOS disrupts the mitochondrial membrane potential, making mitochondria more susceptible to damage, which results in further ROS accumulation and triggers an oxidative stress response, ultimately leading to apoptosis. KEGG pathway enrichment analysis of transcriptomic data from prenylterphenyllin-treated cells demonstrated significant activation of oxidative stress response pathways (Fig. 6A). Moreover, genes involved in promoting ROS production (such as CDKN2D, JUNB, and FES), as well as key downstream transcription factor targets of ROS-including p53 pathway-related genes (CDKN1A and BBC3) and the antioxidant response regulator NFE2L2-were markedly regulated (Fig. 6B, Supplementary Fig. S1A). To explore this, we assessed ROS levels, mitochondrial membrane potential, and mitochondrial superoxide in prenylterphenyllin-treated HCT116, SW620, and SW480 cells. Immunofluorescence staining revealed that prenylterphenyllin treatment significantly decreased mitochondrial mass and membrane potential, while intracellular ROS and mitochondrial superoxide levels were markedly elevated (Fig. 6C–G, Supplementary Fig. S1B–I). Western blot analysis showed a significant increase in Keap1 protein expression, whereas Nrf2 levels were markedly reduced compared to baseline. Furthermore, the expression of HO-1 and NQO-1, key phase II detoxifying enzymes regulated by Nrf2, was consistently downregulated with increasing prenylterphenyllin concentrations (Fig. 6H–J). These results suggest that prenylterphenyllin-induced ROS accumulation triggers oxidative stress, leading to apoptosis in treated cells.

Fig. 6.

Fig. 6

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Prenylterphenyllin induces oxidative stress via the Keap1/Nrf2 pathway. (A) GSEA enrichment of the ROS pathway in prenylterphenyllin-treated HCT116 cells. (B) Expression profiles of ROS modulating genes. (C) Effect of prenylterphenyllin on the ROS levels in HCT116 cells measured using DCFH-DA staining. (D–E) DCFH-DA staining of intracellular ROS levels following prenylterphenyllin treatment. (F–G) Mito-Tracker and MitoSo Red staining of mitochondrial mass and mitochondrial superoxide after prenylterphenyllin exposure. (H–J) Western blot analysis of Keap1 expression and Nrf2, HO-1, and NQO-1 levels in HCT116, SW480, and SW620 cells treated with prenylterphenyllin.

3.7. Prenylterphenyllin inhibits tumor development of CRC in vivo

To evaluate the antitumor activity of prenylterphenyllin in vivo, HCT116 xenografts were established in BALB/c nude mice. The mice were randomly divided into four groups: control, oxaliplatin (5 mg/kg, positive control), low-dose prenylterphenyllin (10 mg/kg), and high-dose prenylterphenyllin (20 mg/kg). Following two weeks of treatment, no significant alterations in body weight were observed across any of the groups (Fig. 7C), indicating that prenylterphenyllin was well tolerated at both tested doses. In contrast, tumor volume and weight were significantly reduced in both prenylterphenyllin and oxaliplatin treated groups compared with control group (Fig. 7A–B, Fig. 7D and E). To further elucidate the antitumor effects, immunohistochemical staining of xenograft tissues was performed. The results revealed that prenylterphenyllin treatment led to a decrease in the proliferation marker Ki67 and an increase in the apoptosis marker cleaved caspase-3, suggesting that tumor cell proliferation was inhibited while apoptosis was enhanced relative to the control group (Fig. 7F and G). It is noteworthy to mention that prenylterphenyllin treatment did not exert any significant cytotoxicity to other tissues, such as, heart, liver, spleen, and kidney as assessed by histological examination (Fig. 7H). Additionally, a subcutaneous tumor model utilizing a murine colorectal cancer (CRC) cell line in immunocompetent mice produced comparable results, further validating the antitumor efficacy of prenylterphenyllin. Taken together, these in vivo studies demonstrate that prenylterphenyllin exerts potent antitumor activity with minimal systemic toxicity (Fig. 7I–M; Supplementary Fig. S2A–K). These findings highlight prenylterphenyllin as a promising therapeutic candidate for colorectal cancer, warranting further mechanistic investigation in the discussion section.

Fig. 7.

Fig. 7

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Prenylterphenyllin inhibits tumor development of CRC in vivo (A) Schematic showing subcutaneous xenograft model of CRC. (B) Quantitative analysis of tumor weights. (C) Body weight monitoring throughout treatment period. (D) Tumor volume growth curves. (E) Tumor growth rate analysis. (F) Representative images of tumor sections stained with H&E, Ki67, and Cleaved caspase-3. (G) Graphs show the quantification of Cleaved caspase-3 and Ki-67 positive cells. (H) Safety assessment through H&E examination of major organs. (I–M) Validation studies in immunocompetent C57BL/6 mice bearing MC38 colorectal tumors. (I) Schematic showing subcutaneous xenograft model of CRC. (J) Quantitative analysis of tumor weights. (K) Body weight monitoring throughout treatment period. (L) Tumor volume growth curves. (M) Tumor growth rate analysis.

3.8. Prenylterphenyllin suppressed lung metastasis of CRC in vivo

To evaluate the potential of prenylterphenyllin in suppressing CRC lung metastasis in vivo, a metastatic model was established through tail vein injection of HCT116 cells into BALB/c nude mice (Fig. 8A). Following tumor cell inoculation, mice received intraperitoneal administration of normal saline (control), prenylterphenyllin (10 mg/kg or 20 mg/kg), or oxaliplatin (5 mg/kg, positive control) for 30 days. As shown in Fig. 8B and C, prenylterphenyllin markedly reduced pulmonary metastasis, with a significant decrease in the number of lung metastatic nodules observed in the high-dose prenylterphenyllin and oxaliplatin groups compared with controls. Consistent with these findings, both lung weight and the lung to body weight ratio were significantly lower in the high-dose prenylterphenyllin group (Fig. 8D and E). Histological evaluation of lung tissues by H&E staining further confirmed that treatment with high-dose prenylterphenyllin substantially inhibited the formation of metastatic foci (Fig. 8F). To validate these observations in immunocompetent settings, additional lung metastasis models were established using murine CRC cell lines (MC38 and CT26). Similar antimetastatic effects of prenylterphenyllin were observed, as evidenced by a significant reduction in metastatic burden (Fig. 8G–L; Supplementary Fig. S3A–F). Collectively, these results reveal that prenylterphenyllin effectively inhibits CRC lung metastasis in both xenograft and syngeneic models, highlighting its potential as an antimetastatic therapeutic candidate. Taken together, all these data suggest that prenylterphenyllin may be mediated the suppression of metastasis, at least in part, modulation of EMT related pathways.

Fig. 8.

Fig. 8

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Prenylterphenyllin suppresses lung metastasis of CRC in vivo. (A) Schematic showing experimental timeline for lung metastasis model. (B) Representative lung images showing metastatic nodules across treatment groups. (C) Quantitative analysis of lung metastatic nodule numbers. (D) Lung weight. (E) Lung/body weight ratios. (F) H&E staining of lung tissues. Quantification of metastatic foci is presented on the right. (G–L) Validation studies in immunocompetent C57BL/6 mice using MC38 cells. (G) Experimental design identical to panel A. (H) Representative lung images showing metastatic nodules across treatment groups. (I) Quantitative analysis of lung metastatic nodule numbers. (J) Lung weight. (K) Lung/body weight ratios. (L) H&E staining of lung tissues. Quantification of metastatic foci is presented on the right.

4. Discussion

CRC persists as a significant global health burden. Despite advancements in early detection and treatment strategies, the prognosis for CRC patients remains poor, especially in advanced and metastatic stages [1,6,7,[45], [46], [47]]. Current therapeutic options, including chemotherapy, are limited by significant side effects, resistance, and insufficient efficacy. This emphasizes the urgent need to develop new therapeutic agents capable of targeting both primary tumors and metastasis. In this study, we investigated the potential of prenylterphenyllin, a natural compound derived from Aspergillus candidus, as a novel therapeutic agent for CRC. Our findings suggest that prenylterphenyllin exerts potent cytotoxic effects on CRC cells, suppresses cell migration and metastasis, and triggers apoptosis through the modulation of energy metabolism and oxidative stress. These results highlight prenylterphenyllin as a promising candidate for CRC therapy, with potential to mitigate chemotherapy resistance and limit metastatic spread.

Energy metabolism reprogramming is a hallmark of cancer, and one of the key metabolic alterations in CRC is the shift from OXPHOS to glycolysis, also commonly known as the Warburg effect. While glycolysis predominates in various types of cancer cells, including CRC, our study demonstrates that both glycolysis and OXPHOS can coexist during CRC progression. Treatment with prenylterphenyllin suppressed OXPHOS in CRC cells, leading to mitochondrial dysfunction and increased production of ROS. This disruption of mitochondrial energy metabolism suggests that prenylterphenyllin promotes oxidative stress and contributes to cell death in CRC cells. The observed elevation in ROS levels was consistent with the inhibition of OXPHOS, leading to mitochondrial damage and a reduction in ATP synthesis. These findings are in line with previous studies that report that metabolic reprogramming, including the suppression of OXPHOS and the accumulation of ROS, contributes to cancer cell death in response to stress or therapeutic agents [[48], [49], [50]].

The role of ROS in cancer is multifaceted. On one hand, ROS are produced during cellular metabolism and can act as signaling molecules that promote cell growth, survival, and adaptation to stress. On the other hand, excessive accumulation of ROS leads to oxidative stress, which can cause damage to cellular components such as lipids, proteins, and DNA. This damage disrupts normal cellular function and can induce cell death through apoptosis. Our study provides sufficient evidence that prenylterphenyllin-induced ROS accumulation plays a key role in triggering apoptosis in CRC cells. RNA sequencing analysis revealed that prenylterphenyllin treatment significantly altered the expression of genes involved in apoptosis regulation. These transcriptional changes suggest that prenylterphenyllin promotes apoptosis in CRC cells by modulating key apoptosis-related pathways, with p53 playing a vital role in mediating this effect [51,52]. The activation of p53 and the induction of apoptosis were confirmed by flow cytometry and Western blot analysis, showing an increase in cleaved caspase-3, a hallmark of apoptosis. These findings are consistent with previous studies demonstrating that p53 activation is a critical mediator of cell death induced by oxidative stress and metabolic dysfunction [53].

In addition to its effects on cell viability and apoptosis, prenylterphenyllin also inhibited the migration and invasion of CRC cells. Metastasis is a leading cause of mortality in CRC patients, making the ability of prenylterphenyllin to suppress cell migration a clinically significant finding. To evaluate the migratory capacity of CRC cells, we employed a cell scratch assay following prenylterphenyllin treatment. Our data demonstrated that prenylterphenyllin significantly reduced the migratory ability of HCT116, SW620, and SW480 cells. This effect is particularly noteworthy given that cancer metastasis is a critical determinant of poor prognosis in CRC patients. Furthermore, we observed downregulation of EMT-associated proteins such as N-cadherin and vimentin, accompanied by upregulation of E-cadherin expression. These findings suggest that prenylterphenyllin may inhibit metastasis by disrupting the EMT process. EMT is essential for cancer cells to acquire migratory and invasive capabilities, and our results indicate that prenylterphenyllin could potentially interfere with this biological process, offering a novel therapeutic strategy for preventing CRC metastasis.

The results of animal experiments further substantiate the promising anticancer potential of prenylterphenyllin. In xenograft models using HCT116 cells, we observed a significant reduction in tumor growth and volume after treatment with prenylterphenyllin. These findings align with the in vitro data and collectively reinforce the therapeutic efficacy of prenylterphenyllin. Notably, prenylterphenyllin showed no significant toxicity in major organs at the tested doses, indicating its favorable safety and tolerability characteristics.‌ Furthermore, prenylterphenyllin demonstrated efficacy in inhibiting lung metastasis in CRC, a critical factor contributing to poor patient prognosis. The reduction in metastatic nodules and lung weight provides additional evidence supporting the potential of prenylterphenyllin as an anti-metastatic agent in CRC therapy.

However, while our study presents compelling evidence for the anticancer effects of prenylterphenyllin, several limitations warrant further investigation. First, although we observed significant changes in gene expression and apoptosis-related proteins, the precise molecular targets of prenylterphenyllin in the mitochondria and its interactions with other signaling pathways remain unclear. Further research is needed to elucidate the specific targets and mechanisms by which prenylterphenyllin modulates OXPHOS and ROS production in CRC cells. Additionally, although our preclinical models show therapeutic potential, clinical trials are necessary to confirm the safety and efficacy of prenylterphenyllin in human patients. It would also be valuable to explore the potential synergistic effects of combining prenylterphenyllin with existing chemotherapeutic agents, as this could provide promising therapeutic strategies for future CRC treatment.

In summary, our findings demonstrate that prenylterphenyllin exerts significant anticancer effects in CRC through inhibiting tumor growth, migration, and metastasis, and inducing apoptosis via the modulation of energy metabolism and oxidative stress. These results collectively suggest that prenylterphenyllin holds substantial therapeutic potential as a novel treatment strategy for CRC, particularly in addressing metastatic progression. Future research priorities should include optimization of clinical dosing strategies and systematic evaluation of drug combination potential. Given its unique pharmacological properties as a bioactive natural product, prenylterphenyllin represents a valuable opportunity for developing innovative CRC treatment therapies.

5. Conclusion

Prenylterphenyllin, a prenylated p-terphenyl from Aspergillus candidus, demonstrates potent anti-CRC activity in both in vitro and in vivo models. It effectively reduces cellular viability, migration and EMT. In xenograft models, it significantly inhibits tumor growth and lung metastasis without significant cytotoxicity to other tissues. Multi-omic integration and functional analyses converge on a mitochondrial/redox-mediated mechanism: prenylterphenyllin disrupts OXPHOS, elevates ROS and mitochondrial superoxide, attenuates the Keap1-Nrf2 antioxidant signaling pathway, and activates p53 signaling, ultimately leading to S-phase cell cycle arrest and apoptosis. Transcriptome and metabolome analyses consistently reveal repression of cell cycle progression and enrichment of p53-related signaling networks, accompanied by extensive perturbation of central carbon metabolism and the TCA cycle. Collectively, these findings reveal that prenylterphenyllin as a promising therapeutic candidate for CRC, particularly in targeting metastatic progression and warrant further investigations to elucidate its direct molecular targets, optimize dosing, pharmacokinetics and evaluate rational combinations with established chemotherapies.

Declaration of generative AI and AI-assisted technologies in the manuscript preparation process

During the preparation of this work the authors used ChatGPT in order to assist in improving the clarity, grammar, and readability of the manuscript. After using ChatGPT, the authors reviewed and edited the content as needed and takes full responsibility for the content of the published article.

Funding

This study was funded by National Natural Science Foundation of China (82230059); National Natural Science Foundation of China (82573130); National Natural Science Foundation of China (82104061); Postdoctoral Fellowship Program of China Postdoctoral Science Foundation (GZB20250491); Natural Science Excellent Youth Foundation of Jiangsu Province (BK20250161); Natural Science Foundation of Jiangsu Basic Research Program (BK20241825); Jiangsu Funding Program for Excellent Postdoctoral Talent (2025ZB138); Jiangsu Province Young Science and Technology Talent Support Project (JSTJ-2025-422); Educational Commission of Liaoning Province of China (JYTQN2023333); Jiangsu Provincial Key Research Development Program of China (BE2022770).

CRediT authorship contribution statement

Yuhan Zhang: Writing – original draft. Yueqing Han: Software. Songmao Li: Formal analysis. Ruimin Shan: Methodology. Ling Lin: Validation. Zhengyu Gu: Visualization. Ruiyu wang: Data curation. Yun Chen: Funding acquisition. Jiao Xiao: Resources. Fangmei An: Software. Chupeng Hu: Investigation. Chunyan He: Formal analysis.

Declaration of competing interest

All authors declare that there are no financial or personal relationships that could inappropriately influence the work reported in this paper.

Footnotes

Appendix A

Supplementary data to this article can be found online at https://doi.org/10.1016/j.redox.2025.103993.

Contributor Information

Yun Chen, Email: chenyun@njmu.edu.cn.

Jiao Xiao, Email: xj110121@126.com.

Fangmei An, Email: fangmeian@njmu.edu.cn.

Chupeng Hu, Email: chupenghu@njmu.edu.cn.

Chunyan He, Email: chunyanhe530@163.com.

Appendix A. Supplementary data

The following is the Supplementary data to this article:

Multimedia component 1
mmc1.doc (4.8MB, doc)

Data availability

Data will be made available on request.

References

  • 1.Sung H., Ferlay J., Siegel R.L., et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2021;71(3):209–249. doi: 10.3322/caac.21660. [DOI] [PubMed] [Google Scholar]
  • 2.Holohan C., Van Schaeybroeck S., Longley D.B., Johnston P.G. Cancer drug resistance: an evolving paradigm. Nat. Rev. Cancer. 2013;13(10):714–726. doi: 10.1038/nrc3599. [DOI] [PubMed] [Google Scholar]
  • 3.Vasan N., Baselga J., Hyman D.M. A view on drug resistance in cancer. Nature. 2019;575(7782):299–309. doi: 10.1038/s41586-019-1730-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Argilés G., Tabernero J., Labianca R., et al. Localised colon cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2020;31(10):1291–1305. doi: 10.1016/j.annonc.2020.06.022. [DOI] [PubMed] [Google Scholar]
  • 5.Li Y., Wang B., Ma F., et al. Proteomic characterization of the colorectal cancer response to chemoradiation and targeted therapies reveals potential therapeutic strategies. Cell Rep. Med. 2023;4(12) doi: 10.1016/j.xcrm.2023.101311. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Shin A.E., Giancotti F.G., Rustgi A.K. Metastatic colorectal cancer: mechanisms and emerging therapeutics. Trends Pharmacol. Sci. 2023;44(4):222–236. doi: 10.1016/j.tips.2023.01.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Cañellas-Socias A., Sancho E., Batlle E. Mechanisms of metastatic colorectal cancer. Nat. Rev. Gastroenterol. Hepatol. 2024;21(9):609–625. doi: 10.1038/s41575-024-00934-z. [DOI] [PubMed] [Google Scholar]
  • 8.Fu Z., Wu T., Gao C., Wang L., Zhang Y., Shi C. AKR1C1 interacts with STAT3 to increase intracellular glutathione and confers resistance to oxaliplatin in colorectal cancer. Acta Pharm. Sin. B. 2024;14(12):5305–5320. doi: 10.1016/j.apsb.2024.08.031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Han Y., Gao Q., Xu Y., et al. Cysteine sulfenylation contributes to liver fibrosis via the regulation of EphB2-mediated signaling. Cell Death Dis. 2024;15(8):602. doi: 10.1038/s41419-024-06997-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Xin Z., Hu C., Zhang C., et al. LncRNA-HMG incites colorectal cancer cells to chemoresistance via repressing p53-mediated ferroptosis. Redox Biol. 2024;77 doi: 10.1016/j.redox.2024.103362. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Hanahan D., Weinberg R.A. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. doi: 10.1016/j.cell.2011.02.013. [DOI] [PubMed] [Google Scholar]
  • 12.De Martino M., Rathmell J.C., Galluzzi L., Vanpouille-Box C. Cancer cell metabolism and antitumour immunity. Nat. Rev. Immunol. 2024;24(9):654–669. doi: 10.1038/s41577-024-01026-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Lyu S., Gildor N., Zhang Q., Liao C. Rewiring cancer metabolism: oncogenic signaling pathways and targeted therapeutics. Sci. China Life Sci. 2025 doi: 10.1007/s11427-025-2979-3. [DOI] [PubMed] [Google Scholar]
  • 14.Denise C., Paoli P., Calvani M., et al. 5-fluorouracil resistant colon cancer cells are addicted to OXPHOS to survive and enhance stem-like traits. Oncotarget. 2015;6(39):41706–41721. doi: 10.18632/oncotarget.5991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Vellinga T.T., Borovski T., de Boer V.C., et al. SIRT1/PGC1α-Dependent increase in oxidative phosphorylation supports chemotherapy resistance of Colon cancer. Clin. Cancer Res. 2015;21(12):2870–2879. doi: 10.1158/1078-0432.CCR-14-2290. [DOI] [PubMed] [Google Scholar]
  • 16.Gonçalves A.C., Richiardone E., Jorge J., et al. Impact of cancer metabolism on therapy resistance - clinical implications. Drug Resist. Updates. 2021;59 doi: 10.1016/j.drup.2021.100797. [DOI] [PubMed] [Google Scholar]
  • 17.Jones N., Blagih J., Zani F., et al. Fructose reprogrammes glutamine-dependent oxidative metabolism to support LPS-induced inflammation. Nat. Commun. 2021;12(1):1209. doi: 10.1038/s41467-021-21461-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.McGuirk S., Audet-Delage Y., Annis M.G., et al. Resistance to different anthracycline chemotherapeutics elicits distinct and actionable primary metabolic dependencies in breast cancer. eLife. 2021;10 doi: 10.7554/eLife.65150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Kao K.C., Vilbois S., Tsai C.H., Ho P.C. Metabolic communication in the tumour-immune microenvironment. Nat. Cell Biol. 2022;24(11):1574–1583. doi: 10.1038/s41556-022-01002-x. [DOI] [PubMed] [Google Scholar]
  • 20.Lin J., Rao D., Zhang M., Gao Q. Metabolic reprogramming in the tumor microenvironment of liver cancer. J. Hematol. Oncol. 2024;17(1):6. doi: 10.1186/s13045-024-01527-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Gorrini C., Harris I.S., Mak T.W. Modulation of oxidative stress as an anticancer strategy. Nat. Rev. Drug Discov. 2013;12(12):931–947. doi: 10.1038/nrd4002. [DOI] [PubMed] [Google Scholar]
  • 22.Kudryavtseva A.V., Krasnov G.S., Dmitriev A.A., et al. Mitochondrial dysfunction and oxidative stress in aging and cancer. Oncotarget. 2016;7(29):44879–44905. doi: 10.18632/oncotarget.9821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Lu Y., Wei W., Li M., et al. The USP11/Nrf2 positive feedback loop promotes colorectal cancer progression by inhibiting mitochondrial apoptosis. Cell Death Dis. 2024;15(12):873. doi: 10.1038/s41419-024-07188-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Chen Y., Lv W., Xu J., et al. Mesenchymal stem cell membrane camouflaged mesoporous polydopamine for Parkinson's disease treatment via alleviating oxidative stress mediated neuroinflammation. Biomaterials. 2026;324 doi: 10.1016/j.biomaterials.2025.123537. [DOI] [PubMed] [Google Scholar]
  • 25.Sies H., Jones D.P. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat. Rev. Mol. Cell Biol. 2020;21(7):363–383. doi: 10.1038/s41580-020-0230-3. [DOI] [PubMed] [Google Scholar]
  • 26.Ling Z., Pan J., Zhang Z., et al. Small-molecule molephantin induces apoptosis and mitophagy flux blockage through ROS production in glioblastoma. Cancer Lett. 2024;592 doi: 10.1016/j.canlet.2024.216927. [DOI] [PubMed] [Google Scholar]
  • 27.Zhang Z., Yang J., Zhou Q., et al. The role and mechanism of the cGAS-STING pathway-mediated ROS in apoptosis and ferroptosis induced by manganese exposure. Redox Biol. 2025;85 doi: 10.1016/j.redox.2025.103761. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Zhang L., Song J., Kong L., et al. The strategies and techniques of drug discovery from natural products. Pharmacol. Ther. 2020;216 doi: 10.1016/j.pharmthera.2020.107686. [DOI] [PubMed] [Google Scholar]
  • 29.Carroll A.R., Copp B.R., Davis R.A., Keyzers R.A., Prinsep M.R. Marine natural products. Nat. Prod. Rep. 2023;40(2):275–325. doi: 10.1039/d2np00083k. [DOI] [PubMed] [Google Scholar]
  • 30.Wei H., Inada H., Hayashi A., et al. Prenylterphenyllin and its dehydroxyl analogs, new cytotoxic substances from a marine-derived Fungus Aspergillus candidus IF10. J. Antibiot. (Tokyo) 2007;60(9):586–590. doi: 10.1038/ja.2007.75. [DOI] [PubMed] [Google Scholar]
  • 31.Peng G., Kurtán T., Mándi A., et al. Neuronal modulators from the coral-associated fungi Aspergillus candidus. Mar. Drugs. 2021;19(5) doi: 10.3390/md19050281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Cai S., Sun S., Zhou H., et al. Prenylated Polyhydroxy-p-terphenyls from Aspergillus taichungensis ZHN-7-07. J. Nat. Prod. 2011;74(5):1106–1110. doi: 10.1021/np2000478. [DOI] [PubMed] [Google Scholar]
  • 33.Morgan E., Arnold M., Gini A., et al. Global burden of colorectal cancer in 2020 and 2040: incidence and mortality estimates from GLOBOCAN. Gut. 2023;72(2):338–344. doi: 10.1136/gutjnl-2022-327736. [DOI] [PubMed] [Google Scholar]
  • 34.Zhou Q., Peng Y., Ji F., et al. Targeting of SLC25A22 boosts the immunotherapeutic response in KRAS-mutant colorectal cancer. Nat. Commun. 2023;14(1):4677. doi: 10.1038/s41467-023-39571-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Eng C., Yoshino T., Ruíz-García E., et al. Colorectal cancer. Lancet. 2024;404(10449):294–310. doi: 10.1016/S0140-6736(24)00360-X. [DOI] [PubMed] [Google Scholar]
  • 36.Lv G., Wang Q., Lin L., et al. mTORC2-driven chromatin cGAS mediates chemoresistance through epigenetic reprogramming in colorectal cancer. Nat. Cell Biol. 2024;26(9):1585–1596. doi: 10.1038/s41556-024-01473-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Yu Q., Yu M., Xie P., et al. Liver regeneration-associated hepatocellular YAP1 activation prevents colorectal cancer liver metastasis through glutamine competition. Sci. Adv. 2025;11(34) doi: 10.1126/sciadv.adw6926. eadw6926. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Lambert J.M.R., Gorzov P., Veprintsev D.B., et al. PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell. 2009;15(5):376–388. doi: 10.1016/j.ccr.2009.03.003. [DOI] [PubMed] [Google Scholar]
  • 39.Li X., Zhou J., Chen Z., Chng W. P53 mutations in colorectal cancer - molecular pathogenesis and pharmacological reactivation. World J. Gastroenterol. 2015;21(1):84–93. doi: 10.3748/wjg.v21.i1.84. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Reinfeld B.I., Madden M.Z., Wolf M.M., et al. Cell-programmed nutrient partitioning in the tumour microenvironment. Nature. 2021;593(7858):282–288. doi: 10.1038/s41586-021-03442-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Du H., Xu T., Yu S., Wu S., Zhang J. Mitochondrial metabolism and cancer therapeutic innovation. Signal Transduct. Targeted Ther. 2025;10(1):245. doi: 10.1038/s41392-025-02311-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Ren L., Meng L., Gao J., et al. PHB2 promotes colorectal cancer cell proliferation and tumorigenesis through NDUFS1-mediated oxidative phosphorylation. Cell Death Dis. 2023;14(1):44. doi: 10.1038/s41419-023-05575-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Dong S., Liang S., Cheng Z., et al. ROS/PI3K/Akt and Wnt/β-catenin signalings activate HIF-1α-induced metabolic reprogramming to impart 5-fluorouracil resistance in colorectal cancer. J. Exp. Clin. Cancer Res. 2022;41(1):15. doi: 10.1186/s13046-021-02229-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Qiu X., Wang A., Wang J., Zhang Z., Tao L. Mitochondrial metabolic reprogramming in colorectal cancer: mechanisms of resistance and future clinical interventions. Cell Death Discov. 2025;11(1):375. doi: 10.1038/s41420-025-02670-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Zhou J., Ji Q., Li Q. Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies. J. Exp. Clin. Cancer Res. 2021;40(1):328. doi: 10.1186/s13046-021-02130-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Liao S., Deng J., Deng M., et al. AFDN deficiency promotes liver tropism of metastatic colorectal cancer. Cancer Res. 2024;84(19):3158–3172. doi: 10.1158/0008-5472.CAN-23-3140. [DOI] [PubMed] [Google Scholar]
  • 47.Yang S., Zhang D., Sun Q., et al. Single-cell and spatial transcriptome profiling identifies the transcription factor BHLHE40 as a driver of EMT in metastatic colorectal cancer. Cancer Res. 2024;84(13):2202–2217. doi: 10.1158/0008-5472.CAN-23-3264. [DOI] [PubMed] [Google Scholar]
  • 48.Wu C., Liu Y., Liu W., et al. NNMT-DNMT1 axis is essential for maintaining cancer cell sensitivity to oxidative phosphorylation inhibition. Adv. Sci. (Weinh.) 2022 doi: 10.1002/advs.202202642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Chen J., Duan S., Wang Y., et al. MYG1 drives glycolysis and colorectal cancer development through nuclear-mitochondrial collaboration. Nat. Commun. 2024;15(1):4969. doi: 10.1038/s41467-024-49221-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Song J., Ham J., Park W., Song G., Lim W. Osthole impairs mitochondrial metabolism and the autophagic flux in colorectal cancer. Phytomedicine. 2024;125 doi: 10.1016/j.phymed.2024.155383. [DOI] [PubMed] [Google Scholar]
  • 51.Ghosh M., Saha S., Li J., Montrose D.C., Martinez L.A. p53 engages the cGAS/STING cytosolic DNA sensing pathway for tumor suppression. Mol Cell. 2023;83(2):266–280.e6. doi: 10.1016/j.molcel.2022.12.023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Di Y., Zhang X., Wen X., et al. MAPK signaling-mediated RFNG phosphorylation and nuclear translocation restrain oxaliplatin-induced apoptosis and ferroptosis. Adv. Sci. (Weinh.) 2024;11(38) doi: 10.1002/advs.202402795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Jiang Z.M., Fang Z.Y., Yang X., et al. Glycyrrhetinic acid ameliorates gastric mucosal injury by modulating gut microbiota and its metabolites via Thbs1/PI3K-Akt/p53 pathway. Phytomedicine. 2025;142 doi: 10.1016/j.phymed.2025.156745. [DOI] [PubMed] [Google Scholar]

Associated Data

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Supplementary Materials

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Data Availability Statement

Data will be made available on request.

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