Zou YF, Zhang YG, Zhao ZC, Li Z, Liu HD, Li QY, Chen ZT, Zhu CJ, Liu HT, Wang JW, Li FY, Wang LJ, Zhang DC, Yang L, Xu H, Xu ZK, Wang S. Impact of non-alcoholic hepatic steatosis on prognosis and clinical outcomes in gastric cancer patients undergoing laparoscopic distal gastrectomy. World J Gastrointest Surg 2025; 17(9): 106198 [DOI: 10.4240/wjgs.v17.i9.106198]
Corresponding Author of This Article
Sen Wang, MD, PhD, Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Gulou District, Nanjing 210029, Jiangsu Province, China. wangsen199206@qq.com
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Retrospective Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Yi-Fan Zou, Yi-Gang Zhang, Zheng Li, Hong-Da Liu, Qing-Ya Li, Ze-Tian Chen, Cheng-Jun Zhu, Hai-Tao Liu, Ji-Wei Wang, Feng-Yuan Li, Lin-Jun Wang, Dian-Cai Zhang, Li Yang, Hao Xu, Ze-Kuan Xu, Sen Wang, Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
Yi-Fan Zou, Yi-Gang Zhang, Zheng Li, Hong-Da Liu, Qing-Ya Li, Ze-Tian Chen, Cheng-Jun Zhu, Hai-Tao Liu, Ji-Wei Wang, Feng-Yuan Li, Lin-Jun Wang, Dian-Cai Zhang, Li Yang, Hao Xu, Ze-Kuan Xu, Sen Wang, Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
Zi-Chu Zhao, The First Clinical College, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
Ze-Kuan Xu, The Institute of Gastric Cancer, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
Ze-Kuan Xu, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu Province, China
Co-corresponding authors: Ze-Kuan Xu and Sen Wang.
Author contributions: Zou YF and Zhang YG were responsible for investigation, formal analysis and writing the original draft; Zou YF was responsible for the figure plotting, preparation and submission of the manuscript. Zhang YG search the literature and drafted the major part of the discussion section. Both co-first authors (Zou YF and Zhang YG) made substantial and indispensable contributions to the study. Zhao ZC revised and validated the conclusions. Li Z, Liu HD, Li FY, Wang LJ, Zhang DC, Yang L and Xu H provided the data resources of all clinical samples; Li QY was mainly responsible for patient follow-up and data curation; Chen ZT, Zhu CJ, Liu HT and Wang JW reviewed and validated all data and results; Both Xu ZK and Wang S, who were co-corresponding authors in the current study, conceptualized the study and supervised all procedures during the implementation of the research. Xu ZK focuses on the perioperative management of patients receiving gastrectomy based on personalized risk stratification. Considering that NAFLD is a risk factor for gastric cancer, he thought whether patients with or without NAFLD would have distinct clinical outcomes, which made him launch this study. Wang S acquired the funding for the study, which ensured the research could be developed smoothly. Both co-corresponding authors (Xu ZK and Wang S) were crucial for the implementation and final publication of this manuscript.
Supported by China Postdoctoral Science Foundation, No. 2021TQ0132; and The Youth Fund Program for National Natural Science Foundation of China from the First Affiliated Hospital of Nanjing Medical University, No. PY2021032.
Institutional review board statement: This investigation was approved by the Institutional Ethics Committee of Nanjing Medical University.
Informed consent statement: The need for patient consent was waived due to the retrospective nature of the study.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The original data used in the study will be shared upon reasonable request at wangsen199206@qq.com.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Sen Wang, MD, PhD, Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Gulou District, Nanjing 210029, Jiangsu Province, China. wangsen199206@qq.com
Received: February 19, 2025 Revised: April 12, 2025 Accepted: July 21, 2025 Published online: September 27, 2025 Processing time: 217 Days and 21.9 Hours
Abstract
BACKGROUND
Non-alcoholic fatty liver disease (NAFLD) is increasingly recognized for its role in the pathogenesis of various cancers. However, its impact on gastric cancer (GC) outcomes, particularly in patients undergoing laparoscopic distal gastrectomy (LDG), remains unclear.
AIM
To investigate the clinical and prognostic impacts of NAFLD on GC patients undergoing LDG.
METHODS
In this retrospective cohort study, we collected clinical data from 1122 GC patients who underwent LDG at the Gastric Cancer Center of the First Affiliated Hospital of Nanjing Medical University between January 2020 and December 2022. Propensity score-matching (PSM) was used to mitigate the bias to compare the oncological and surgical outcomes between the two groups. Survival analysis was also performed to evaluate NAFLD as a prognostic factor.
RESULTS
PSM yielded a balanced cohort of 260 patients (52 with NAFLD and 208 controls) from the original cohort. No differences in clinicopathological characteristics, including surgery time, complications, T stage, N stage, p-tumor-node-metastasis stage, neural invasion, vascular invasion, total number of retrieved lymph nodes, positive retrieved lymph nodes and positive lymph nodes rate, were observed between the two groups. Overall survival was comparable between two groups (Log-rank P = 0.49), whereas progression-free survival (PFS) in the NAFLD group was inferior to that in the control group (Log-rank P = 0.016). Univariable Cox regression analysis further confirmed that NAFLD was an unfavorable prognostic factor for PFS.
CONCLUSION
GC patients with NAFLD exhibited inferior PFS, suggesting that addressing NAFLD-related metabolic alterations may enhance clinical outcomes. Future investigations should explore the mechanistic links between NAFLD and GC progression and consider integrated therapeutic strategies.
Core Tip: This is a retrospective single-center observational study to investigate the potential impacts of Non-alcoholic fatty liver disease (NAFLD) on gastric cancer (GC) patients receiving laparoscopic distal gastrectomy. Propensity score-matching analysis was utilized to generate a balanced cohort and we observed no difference in major clinicopathological characteristics between GC patients with and without NAFLD. Moreover, survival analysis indicated that GC patients with hepatic steatosis experience inferior progression-free survival (PFS) compared with those without NAFLD. In summary, NAFLD is a predictive factor of PFS and could be further employed in the clinical management of GC.
Citation: Zou YF, Zhang YG, Zhao ZC, Li Z, Liu HD, Li QY, Chen ZT, Zhu CJ, Liu HT, Wang JW, Li FY, Wang LJ, Zhang DC, Yang L, Xu H, Xu ZK, Wang S. Impact of non-alcoholic hepatic steatosis on prognosis and clinical outcomes in gastric cancer patients undergoing laparoscopic distal gastrectomy. World J Gastrointest Surg 2025; 17(9): 106198
Gastric cancer (GC) is a significant global health concern, ranking as the 5th most common malignancy and the 4th leading cause of cancer-related mortality worldwide[1]. In China, a substantial proportion of overall cancer incidence occurs, with recent statistics indicating a GC age-adjusted incidence rate of 19.11 per 100000 person-years for GC[2]. For resectable GC patients, radical gastrectomy is considered the primary treatment strategy and the survival of patients is largely dependent on the stage of the tumor[3,4]. However, postoperative recurrence and unfavorable complications continue to pose significant challenges to the clinical outcomes of patients undergoing gastrectomy. Therefore, early identification and stratification of postoperative patients are pivotal for predicting surgical outcomes and optimizing clinical management.
GC is highly heterogeneous and influenced by both genetic and environmental factors, which affect disease initiation, progression and clinical outcomes[5-7]. For instance, Helicobacter pylori (H. pylori) infection is a well-established global risk factor for GC, with diverse pathogeneses[8]. Moreover, H. pylori infection can shape the tumor immune landscape, potentially affecting the efficacy of immunotherapy[9,10]. Specific genetic variants identified through genome-wide association studies have also been shown to affect disease susceptibility and prognosis[11,12]. In the clinical context, the 8th American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system is widely employed as the instructor of GC treatment, yet the criteria alone cannot provide adequate information for surgical outcome prediction[13-15].
Non-alcoholic fatty liver disease (NAFLD) is a prevalent cause of liver disease worldwide, characterized by chronic development stages and systematic metabolic dysregulation[16,17]. In addition to common chronic liver diseases, recent studies have focused on the multifaceted role of NAFLD in extrahepatic diseases, including diabetes, cardiovascular diseases and cancers[18,19]. Cohort studies have linked NAFLD with pancreatic, colorectal and stomach cancers[20-22]. In addition, NAFLD has been identified as a risk factor for adenoma recurrence in the elderly population following colonoscopy[23] and for liver metastasis after colorectal cancer surgery[24]. However, the role of NAFLD in the postoperative dynamics and clinical characteristics of GC patients remains unclear.
In the present study, we conducted a single-center retrospective study using a propensity score matching (PSM) method to explore the oncological and survival outcomes of GC patients with and without NAFLD. Our analyses incorporated multiple clinical and laboratory parameters to identify potential biomarkers as well as implications for optimal treatment strategies for the subgroup of NAFLD-related GC patients.
MATERIALS AND METHODS
Study design
This retrospective study was conducted in a single center via PSM. We aimed to compare the oncological and surgical outcomes of GC patients with NAFLD who received laparoscopic distal gastrectomy (LDG) with those of patients without NAFLD. The flowchart of the study is shown in Figure 1.
Figure 1 Flow diagram of the patient selection, diagnostic stratification and propensity score matching procedures.
ESD: Endoscopic submucosal dissection; CT: Computer tomography; NAFLD: Alcoholic fatty liver disease.
This study enrolled GC patients (n = 1183) who received LDG at the Gastric Cancer Center of the First Affiliated Hospital of Nanjing Medical University between January 2020 and December 2022. The criteria for patient selection were patients aged 18-80 years old with gastric tumors who underwent LDG with lymph node dissection. The candidate patients were further filtered by the following exclusion criteria: Patients who underwent other combined surgeries; patients whose critical baseline, clinical outcome or pretreatment imaging data were missing; patients who were previously diagnosed with alcoholic fatty liver disease; patients who were not pathologically identified as having gastric adenocarcinoma; and patients who underwent additional gastric surgery after endoscopic submucosal dissection. A total of 1122 patients were ultimately enrolled.
Cohort definition
Computer tomography (CT) scans of these patients were used for the diagnosis of hepatic steatosis and the method was proven to be reliable and reproducible in previous studies[25]. The images were artificially recognized by at least two experienced radiologists independently to ensure the accuracy and a further consultation was required if conflicting results or difficult cases were encountered. The spleen measurement was used as reference to infer the fat content in the liver. The remaining patients who met the inclusion criteria (n = 1122) were classified into the NAFLD group (n = 52) or the control group (n = 1070) before PSM. The patients all received LDG with standard lymphadenectomy. The laparoscopic approach was total laparoscopic or laparoscopic-assisted. The digestive tract reconstruction techniques included Billroth-I, Billroth-II, Roux-en-Y and uncut Roux-en-Y anastomosis. All of the above surgical treatments were in compliance with the Japanese Gastric Cancer Treatment Guidelines[26].
Clinicopathological and survival information
We obtained the following baseline characteristics of all included patients: Age, sex, body mass index (BMI) and preoperative serum carcinoembryonic antigen (CEA), carbohydrate 19-9 (CA199) and carbohydrate 72-4 (CA724) levels. The following clinicopathological features were further collected: Surgery time (minute), postoperative complications, pT stage, pN stage, pTNM stage, neural invasion, vascular invasion, total retrieved lymph nodes and positive retrieved lymph nodes. Additional clinical laboratory parameters were also included: Routine blood tests, liver and renal function and three nutritional indices, including prognostic nutritional index (PNI)[27], the nutritional risk index (NRI)[28] and the controlling nutritional status (CONUT) score[29]. Triglyceride-glucose index (TyG) was calculated as ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2][30]. The fibrosis-4 score (FIB-4 score) was calculated as [age (years) × aspartate transaminase (U/L)]/[alanine transaminase (U/L)0.5 × platelet (109/L)] for assessment of liver fibrosis[31]. The remaining parameters are supplied in the supplementary section.
Follow-up was mainly carried out by telephone enquiry and outpatient review every 3 months. The primary outcomes included overall survival (OS) and progression-free survival (PFS). OS was calculated from the date of GC operation until the date of death, censoring those who were alive at the last follow-up. PFS was calculated from the date of gastrectomy until the date of recurrence or disease progression proven by clinical evidence, censoring patients who were alive and disease free at the last follow-up.
Statistical analysis
To reduce selection bias and ensure comparability between the NAFLD and the control groups, PSM without replacement was performed at a 1:4 ratio with a 0.2 caliper width, which included covariates such as age, sex, T stage, N stage, anastomosis techniques and laparoscopic approach. We checked the statistic balance between two groups before and after PSM analysis by calculating absolute standardized mean difference (SMD). An SMD threshold of 0.2 was considered to detect substantial imbalance.
Categorical variables are presented as frequencies and percentages, analyzed using either the χ2 test (or Fisher’s exact test depending on the situation). Continuous variables were compared via the Wilcoxon rank-sum test. The differences in OS and PFS between groups were estimated via the Kaplan-Meier method and compared via the Log-rank test between groups. Uni- and multivariable Cox regression were utilized to assess the effects of clinicopathological covariates on OS and PFS. A two-tailed P value < 0.05 was considered statistically significant. All statistical analyses were implemented with R 4.2.2 software (R Foundation, Vienna, Austria).
RESULTS
The baseline characteristics between NAFLD and control groups
The flowchart of the patient selection process is presented in Figure 1, and the detailed information of the excluded samples is organized in Supplementary Table 1. The baseline characteristics of all GC patients with and without NAFLD were provided in Table 1. The distribution of sex and age in the two groups were balanced. We found that the BMI of GC patients with NAFLD is elevated (26.6 vs 23.9, P < 0.001), which indicated that the systemic metabolic dysregulation is involved in the development of NAFLD[16]. Moreover, overweight/obesity or a high BMI is recognized as a major risk factor for GC[32,33]. We therefore speculated that overweight/obesity and NAFLD are tightly linked to each other and jointly lead to the occurrence of GC, the mechanisms of which remain further investigation. In addition, there was no difference in the levels of three major tumor biomarkers (CEA, CA724 and CA199) between the two groups.
Table 1 Baseline characteristics before and after propensity score-matching, n (%).
The clinicopathological characteristics between NAFLD and control groups
All patients received LDG (total laparoscopic or laparoscopic-assisted) and the reconstruction included four techniques (Billroth-I, Billroth-II, Roux-en-Y and uncut Roux-en-Y), which were all incorporated into the PSM procedure. The detailed clinicopathological characteristics are presented in Table 2. In the analyses before PSM, we observed that patients with NAFLD had significantly fewer retrieved lymph nodes (39.2 vs 42.5, P = 0.04) and these patients were found to have an earlier N stage (P = 0.028). A previous study indicated that there might be fewer retrieved lymph nodes in patients with a high BMI[34], whereas an updated meta-analysis proved that the conclusion is unsound[35]. We reasoned that the difference observed in our study might be due to the greater volume of visceral fat in patients with NAFLD or bias caused by a small sample size. Reassuringly, no difference was detected in the two variables after PSM analysis, indicating the persuasiveness of subsequent conclusions. All other parameters including surgery time, complication rate, T stage, pTNM stage, neural invasion, vascular invasion and positive lymph nodes were also comparable before and after PSM, suggesting that NAFLD might have minor impacts on these clinical features.
Table 2 Clinicopathological characteristics before and after propensity score-matching adjusting for major clinical parameters including sex, age, pathological T stage, pathological N stage, reconstructive techniques and laparoscopic approach.
Comparison of laboratory examinations between NAFLD and control groups
Several biochemical test components were exploited in the panel test for predicting non-alcoholic steatohepatitis, whereas no serum indicators were discovered to discriminate NAFLD patients with GC. To identify the potential biomarkers for these patients, we further compared several laboratory examination parameters between two groups, including the routine blood tests, liver and renal function and nutritional indices between the two groups in the PS-matched cohort. Among parameters measured via blood routine tests, the mean corpuscular volume of GC patients with NAFLD was lower than that of the control individuals (88.96 vs 90.39, P = 0.019; Supplementary Table 2). In addition, with respect to liver and renal function parameters, these patients had higher levels of glucose (5.33 vs 5.11, P = 0.005), alanine aminotransferase (31.88 vs 19.74, P = 0.004) and aspartate transaminase (26.98 vs 22.61, P = 0.034; Supplementary Table 3). Notably, GC patients with NAFLD were presented relatively high levels of γ-glutamyl transpeptidase (47.95 vs 31.51, P = 0.054) and TyG index (8.75 vs 8.58, P = 0.063) but similar levels of FIB-4 scores (1.63 vs 1.57, P = 0.785). There was no difference in other laboratory examinations.
NAFLD is also featured with disturbed metabolic and nutritional status[36,37]. Therefore, we investigated several objective assessment indices that evaluate the nutritional status of postoperative patients, including PNI, NRI and CONUT score. We observed that GC patients with NAFLD had higher NRI scores (110.60 vs 104.58, P = 1.14 × 10-6) and lower CONUT score (1.33 vs 1.81, P = 0.025; Supplementary Figure 1), which seemed credible considering that BMI was also higher in these patients and suggested that NAFLD-related GC patients had better nutritional status. These findings suggest that GC patients with NAFLD exhibit altered liver function and nutritional status, while the extent of liver fibrosis remains comparable between the two groups.
Survival analysis of GC patients with or without NAFLD
The median follow-up time of all patients receiving LDG was 31.5 months. Survival analysis of the entire cohort revealed no difference in the OS (P = 0.698) between the NAFLD and control groups, whereas the patients in NAFLD group had inferior PFS (P = 0.001) compared with those in the control group (Figure 2A and B). After PSM analysis, the Kaplan-Meier curves (Figure 2C) demonstrated comparable OS (P = 0.491) between NAFLD and control groups. Notably, we still observed that patients with NAFLD were more likely to experience disease recurrence (Figure 2D), manifested as inferior PFS during the follow-up (P = 0.016). Stratified analyses were further performed based on the basis of the T stage of patients (early stage: T1-T2; advanced stage: T3-T4). We found that OS was comparable between patients with or without NAFLD diagnosed with early-stage (P = 0.274) and advanced-stage GC (P = 0.154, Supplementary Figure 2A and B). In addition, early-stage GC patients with NAFLD exhibited inferior PFS compared with those without NAFLD (P = 0.024; Supplementary Figure 2C), whereas NAFLD status had a minor effect on the PFS of locally advanced GC patients receiving LDG (P = 0.258; Supplementary Figure 2D).
Figure 2 Kaplan-Meier curves.
A: Overall survival; B: Progression-free survival in patients with and without non-alcoholic fatty liver disease before propensity score matching; C: Overall survival; D: Progression-free survival in patients with and without non-alcoholic fatty liver disease after propensity score matching. PSM: Propensity score-matching; NAFLD: Alcoholic fatty liver disease.
We also conducted univariate and multivariate Cox proportional hazard analyses in the original cohort as well as in the matched samples. We found that the age, T stage, N stage, AJCC pTMN stage, vascular invasion, neural invasion, the number of positive retrieved lymph nodes and positive lymph nodes were significantly correlated with OS (Supplementary Table 4). In the multivariable regression analysis, the independent factors for OS were age, T stage and number of positive retrieved lymph nodes. In terms of the analysis for PFS, similar results were observed except that NAFLD status and the FIB-4 score were identified as additional prognostic factors in the univariable regression analysis (Supplementary Table 5). However, when all the significant factors were considered, only NAFLD status remained an independent predictor of PFS, whereas the FIB-4 score was not. In the PS-matched cohort, we observed that NAFLD was a PFS-related prognostic factor, whereas the FIB-4 score was identified as an influencing factor for OS (Table 3). Further analysis indicated that age and T stage were two reliable indicators of postoperative survival and recurrence and NAFLD was not an independent prognostic factor for PFS of LDG patients (Supplementary Table 6).
Table 3 Univariable Cox regression model for overall survival and progression-free survival in the propensity score-matched samples.
In this study, we investigated the impact of NAFLD on the outcomes of GC patients undergoing LDG. Our findings provide significant insights into the postoperative and oncological trajectories of GC patients with NAFLD, a topic that has not been extensively studied. Although our analysis indicated that OS did not significantly differ between patients with and without NAFLD, those with NAFLD exhibited poorer PFS. This disparity suggests that NAFLD may increase the risk of disease recurrence after surgery, highlighting important clinical implications. For example, patients with NAFLD may benefit from more intensive surveillance and follow-up to enable early detection of recurrence and timely intervention. Additionally, nutritional and lifestyle interventions, such as weight management and dietary modifications, should be prioritized for postsurgical patients with NAFLD to improve both liver health and cancer outcomes. For drug target development, we reasoned that the potential mechanism behind this increased risk could be the complex metabolic disturbances associated with NAFLD, which include insulin resistance (IR), chronic inflammation, and lipid perturbations. These factors may collectively create a microenvironment conducive to tumor recurrence or progression, which is extensively discussed below.
IR, a hallmark of NAFLD, initiates a cascade of metabolic and inflammatory changes that significantly contribute to tumorigenesis[38]. One of the primary consequences of IR is hyperinsulinemia, which promotes tumorigenesis by activating the PI3K/AKT and MAPK signaling pathways. These pathways are well-documented for their roles in driving cell proliferation, inhibiting apoptosis, and sustaining cancer cell survival[39,40]. Additionally, elevated circulating levels of insulin-like growth factor-1, which is frequently observed in NAFLD patients with IR, further stimulate gastric epithelial cell proliferation and transformation, thereby facilitating the development of GC[41,42]. The hyperinsulinemic state associated with NAFLD also induces angiogenesis through the activation of vascular endothelial growth factor, which supports tumor growth and recurrence[43,44]. Evidence from a prospective cohort study demonstrated that the C-reactive protein-triglyceride-glucose index, an indicator of systemic IR, was correlated with poorer survival outcomes in GC patients[45]. Furthermore, a retrospective analysis involving 215 GC patients and 827 healthy individuals revealed that the TyG index, another index of IR, was significantly higher in GC patients than in control individuals[46]. These findings underscore the central role of IR in linking NAFLD to GC and emphasize the critical importance of metabolic interventions to prevent cancer development and recurrence in NAFLD patients.
NAFLD is marked by the activation of both systemic and local inflammatory pathways, which are driven primarily by pro-inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-6 (IL-6), and C-reactive protein. These inflammatory mediators contribute to a tumorigenic environment by inducing persistent oxidative stress, DNA damage, and epigenetic alterations, which are pivotal in the initiation of various cancers, including GC[47]. The chronic inflammation associated with NAFLD also affects the gut-liver axis, leading to alterations in the gut homeostasis and intestinal barrier function[48]. Disturbed gut microbiota and chronic inflammation can act interactively to promote liver oncogenesis via GPR43/IL-6/JAK1/STAT3 inflammatory pathway[49] and cholesterol-related cell proliferation[50]. Notably, patients undergoing gastric surgery and concomitant gastrointestinal tract reconstruction presented perturbed post-surgery bacterial profiles. Alterations in the gut microbiome could enhance bacterial translocation and dysbiosis, both of which are implicated in gastric carcinogenesis[51-53]. Studies have indicated that microbial dysbiosis may contribute to the development of GC through the activation of pro-inflammatory pathways, the inflammasome, and the innate immune system[54]. In recurrent cases, the inflammatory environment fostered by NAFLD promotes resistance to anticancer therapies by enabling immune evasion and the survival of cancer stem cells[55,56]. These findings implicate the potential role of chronic inflammation and microbiota alterations in GC recurrence among NAFLD patients receiving LDG, underscoring the necessity of further experiments for mechanism exploration and drug target prioritization.
NAFLD is characterized by dysregulated lipid metabolism, which significantly contributes to tumor development and recurrence, particularly in patients with GC. The hallmark lipid perturbations in NAFLD include increased lipogenesis, altered fatty acid oxidation, and the excessive accumulation of toxic lipid species such as ceramides and diacylglycerols[57]. These lipid abnormalities drive oncogenesis through multiple mechanisms, including chronic oxidative stress, inflammation, and mitochondrial dysfunction[58,59]. Excess lipid deposition in NAFLD activates signaling pathways such as AMPK/SREBP1 and PPAR pathways, which promote cell proliferation, angiogenesis, and the survival of GC cells[60,61]. Furthermore, lipid accumulation leads to lipotoxicity, triggering endoplasmic reticulum stress and the subsequent activation of the unfolded protein response. This response has been shown to increase cancer cell resistance to therapy and contribute to tumor recurrence[62,63]. Additionally, dysregulated cholesterol metabolism in NAFLD facilitates gastric tumorigenesis by promoting membrane fluidity and facilitating oncogenic signaling[64,65]. Collectively, these NAFLD-associated lipid perturbations create a tumor-permissive environment that fosters both the initial development and recurrence of GC. These findings highlight the importance of metabolic profiling experiments in NAFLD-related malignancies for further clinical investigations and the targeting of lipid metabolism in cancer prevention and treatment.
To our knowledge, our study represents the first comprehensive analysis of the impact of NAFLD on the prognosis of GC patients, specifically focusing on those undergoing LDG utilizing the methodology of PSM analysis to mitigate bias. By establishing a significant correlation between NAFLD and poorer PFS, particularly in early-stage GC, our findings underscore that the integration of metabolic risk assessment into post-surgery management could optimize oncological outcomes, paving the way for future research into molecular pathogenic mechanisms and targeted therapeutic strategies in NAFLD-related malignancies.
However, our study also has several limitations, primarily due to its retrospective design and reliance on a single-center dataset. To address these limitations, future prospective studies are necessary to validate our results and investigate the underlying biological mechanisms more thoroughly. Moreover, the diagnosis of NAFLD relied solely on CT scans, which overlooked the complexity of NAFLD severity and associated comorbidities, such as metabolic syndrome and cirrhosis. This limitation may have introduced confounding effects in the interpretation of our findings. Additionally, obtaining long-term data on survival and comorbidities through longitudinal studies, as well as evaluating the impact of targeted interventions for NAFLD in the clinical management of GC patients, could provide deeper insights. Finally, a notable limitation of our study is its exclusive focus on GC patients undergoing LDG, which may limit the generalizability of the findings.
CONCLUSION
In summary, our findings reveal that GC patients with NAFLD experience significantly poorer PFS, particularly those with early-stage disease, underscoring the importance of considering NAFLD status in the prognostic assessment and management of GC patients undergoing LDG. The implementation of tailored strategies that address the metabolic derangements associated with NAFLD may enhance patient outcomes and should be incorporated into comprehensive cancer care models. This study contributes to the expanding body of evidence highlighting the intersection between metabolic health and cancer progression, advocating for a multidisciplinary approach to the treatment of GC in patients with NAFLD.
ACKNOWLEDGEMENTS
We would also like to thank the Core Facility of the First Affiliated Hospital of Nanjing Medical University for its help in the collection of clinical information.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade B, Grade B
Novelty: Grade B, Grade C
Creativity or Innovation: Grade B, Grade C
Scientific Significance: Grade B, Grade B
P-Reviewer: Shanka NY; Yu LN S-Editor: Li L L-Editor: A P-Editor: Zhang YL
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