Table 1.

Chronological Overview of Key Studies Investigating Lipid Peroxidation, Lipid Metabolism, and Serum Lipid Profiles in Oral Cancer

Authors	Year	Study population	Key findings
Nagini et al.[210]	1998	24 newly diagnosed stage IV oral cancer patients and 24 normal subjects	• Significantly decreased lipid peroxidation in tumor tissue • Elevated glutathione levels and glutathione peroxidase activity • Decreased superoxide dismutase and catalase activities • Findings suggest decreased susceptibility of oral tumor tissue to lipid peroxidation
Saroja et al.[179]	1999	Tumor tissues from 33 OSCC patients compared with normal tissues	• Decreased lipid peroxidation in oral tumor tissue • Significant decrease in phospholipids • Increased cholesterol and cholesterol/phospholipid ratio • Decreased free fatty acids • Elevated glutathione concentration and increased activities of glutathione peroxidase and glutathione-S-transferase in tumor tissues
Baskar et al.[211]	2004	20 subjects (10 healthy adults, 10 oral cancer patients)	• Phase delay in erythrocyte TBARS levels and enzymatic antioxidant activities in oral cancer patients compared to healthy subjects • Desynchronization of circadian rhythms in lipid peroxidation and antioxidant enzymes in oral cancer patients • Altered temporal patterns in superoxide dismutase, glutathione peroxidase, and catalase activities in cancer patients
Rajpura et al.[212]	2005	41 OSCC patients, 20 oral precancerous condition patients, 20 healthy controls	• Significant elevations in total sialic acid (TSA) and lipid-bound sialic acid (LSA) levels in OSCC patients compared to controls and OPC patients • Progressive increase in TSA and LSA with advancing clinical stage of OSCC • No significant association with histopathological grade
Manoharan et al.[213]	2005	10 OSCC patients, 10 age-matched healthy controls	• Circadian alterations in plasma lipid peroxidation and antioxidants in OSCC patients • Acrophase of plasma TBARS delayed by 2.5 h in OSCC patients (19:14 h vs 16:40 h in controls) • Acrophase of GSH delayed by 2 h in OSCC patients (02:00 vs 00:00 in controls) • Acrophase of GPx delayed by 3.5 h in OSCC patients (02:32 h vs 22:55 h in controls) • Decreased mesor values for GSH and GPx in OSCC patients
Manoharan et al.[63]	2005	48 male oral cancer patients (stages II-IV) and 16 healthy subjects	• Elevated lipid peroxidation and decline in antioxidant status in oral cancer patients • TBARS levels gradually increased while antioxidants gradually reduced from stage II to stage IV • Alterations in plasma lipid peroxidation may be related to compensatory changes in antioxidant defense system
Patel et al.[64]	2007	190 subjects (50 healthy controls, 140 OSCC patients)	• Lower thiol levels in controls with tobacco habits, oral cancer patients, and malignant tissues • Higher tobacco exposure in oral cancer patients than controls with tobacco habits • Controls with lower thiol levels and high tobacco exposure showed elevated risk of oral cancer • Patients with higher lipid peroxidation showed poorer overall survival • Patients with lower thiol and total antioxidant status showed poorer overall survival
Ghosh et al.[214]	2011	30 OSCC patients, 20 tobacco habituates, 20 healthy controls	• Significant decrease in serum total cholesterol and triglyceride levels in OSCC patients compared to healthy controls • Significantly lower HDL levels in tobacco habituates compared to controls • Significantly lower total cholesterol, LDL levels, and TC:HDL ratios in OSCC patients compared to tobacco habituates • Significant increase in HDL levels in OSCC patients compared to tobacco habituates
Chawda et al.[16]	2011	25 OSCC patients, 5 healthy controls	• Significantly lower levels of total lipids, cholesterol, and HDL in oral cancer patients compared to controls • No significant differences in LDL and VLDL between groups • No significant differences in lipid profiles between histological grades of OSCC
Taqi et al.[215]	2012	95 subjects (35 healthy controls, 30 oral precancer, 30 OSCC)	• Mean values of serum sialic acid (total and lipid bound) in oral cancer were significantly higher than control and the precancer group • Progressive rise in total and lipid-bound sialic acid with clinical stage of cancer • Serum sialic acid levels differentiated between patients with oral precancer and oral cancer • Sialic acid could be used to monitor response to therapy and assess cancer staging
Kumar et al.[44]	2012	30 healthy controls, 30 oral leukoplakia patients, 30 tobacco abusers, 30 OSCC patients	• TC, HDL, and LDL were significantly lower in OSCC group compared to controls • Inverse relationship between serum lipid profile and oral cancer • No significant reduction in lipid profile in oral leukoplakia group • TC and HDL decreased marginally with loss of tumor differentiation • No correlation between mean serum lipid profiles and degree of dysplasia in leukoplakia
Singh et al.[216]	2013	50 OSCC patients, 25 healthy controls	• Significant decrease in TC, HDL-C, and TGL in OSCC group compared to controls • No significant correlation of lipid profile with histological grading • No statistical difference in lipid profiles between tobacco and non-tobacco users • Inverse relationship between serum lipid profile and oral cancer
Mehta et al.[217]	2014	60 OSMF/precancerous patients, 60 OSCC patients, 60 controls	• Significant reduction in plasma TC, HDL-C, LDL-C, VLDL and triglycerides in precancerous and cancerous groups compared to controls • On comparison between precancerous and cancerous groups, significant decrease observed in cancerous group • Changes in lipid levels may have early diagnostic or prognostic role
Ganesan et al.[65]	2014	50 patients (20 controls, 10 with oral leukoplakia, 20 with OSCC)	• Significantly elevated levels of lipid peroxides in saliva, serum, and tissue in oral leukoplakia and OSCC compared to controls • Higher lipid peroxidation levels in OSCC than in oral leukoplakia • Increased MDA levels in patients with smoking and chewing habits • No significant difference in MDA levels between genders • Lower levels of antioxidants in carcinogenesis
Rasool et al.[218]	2014	30 healthy controls, 30 oral leukoplakia patients, 40 OSCC patients	• Significantly increased levels of MDA and sialic acid in plasma of OSCC patients compared to controls • Significantly decreased antioxidant levels in OSCC patients • Salivary MDA is a better diagnostic tool compared to blood MDA • β-2MG in blood is better diagnostic marker compared to β-2MG in saliva
Metgud & Bajaj[66]	2014	30 healthy controls, 30 oral leukoplakia patients, 40 OSCC patients	• Enhanced MDA levels in saliva and serum in oral leukoplakia and OSCC patients compared to controls • Significant decreases in serum and salivary GSH levels in oral leukoplakia and OSCC patients • Augmentation of oxidative stress in blood and saliva reflected by increase in MDA and decrease in GSH levels • No significant correlation between histopathological grades of leukoplakia and MDA/GSH levels
Shetty et al.[68]	2014	65 healthy controls, 115 potentially malignant disorders (PMD), and 50 OSCC patients	• Consistent elevation in salivary MDA levels in healthy controls with tobacco habits, PMD subjects, and OSCC subjects • Significant elevation in salivary MDA in PMD and OSCC groups compared to healthy controls • Salivary malondialdehyde analysis can be used as an efficient, non-invasive tool for early diagnosis
Acharya et al.[41]	2016	90 untreated OSCC patients and 30 healthy controls	• Significant decreases in serum TC, HDL, and LDL in OSCC patients vs controls • No significant correlation between lipid profile and tumor stage, grade, or lymph node metastasis • Tobacco users showed lower TC, LDL, and TG values than non-tobacco users
Subbulakshmi et al.[76]	2017	20 OSMF patients, 20 OSCC patients, 20 controls	• Significant decrease in serum total cholesterol, HDL-C, and LDL-C in OSMF and OSCC compared to controls < br > • No significant difference in triglyceride levels • Decreased lipid levels in patients suggest utilization of lipids by cells during cancer process
Wang et al.[219]	2017	50 OSCC patients, 50 healthy controls	• Identified 20 differential lipids between OSCC and controls • Decreased glycerophospholipids (especially phosphatidylcholine and phosphoethanolamine plasmalogens) • Increased sphingolipids (ceramides and sphingomyelins) Identified 12 lipids associated with pathological staging that could discriminate early stage from advanced stage patients
Hu et al.[75]	2019	576 T1/2N0M0 OSCC patients without prediagnosis weight loss	• Obesity was an independent risk factor for progression-free survival and disease-specific survival in early-stage OSCC • 72 dysregulated lipid metabolism-related genes identified in OSCC • A combining signature of TGFB1, SPP1, and SERPINE1 was defined as a biomarker for prognostic prediction
Singh et al.[77]	2021	129 patients (25 healthy controls, 26 OSMF cases, 26 leukoplakia, 52 oral cancer)	• No statistically significant difference in serum and salivary total cholesterol and HDL levels among all groups • Statistically significant difference in salivary triglyceride levels • Significant positive correlation between serum and salivary lipid levels • Salivary lipids can be used as a non-invasive alternative to serum lipid estimation • No association established between lipid profiles and oral precancer/cancer
Alazzawi et al.[43]	2022	22 OSCC patients, 22 healthy controls	• Significant decrease in serum cholesterol, triglyceride, HDL-C, LDL-C, and VLDL in OSCC patients compared to controls • First to report significant decrease in serum Apolipoprotein C-1 (ApoC-1) levels in OSCC patients • Higher ApoC-1 level in patients with vascular invasion • No significant correlation of serum ApoC-1 with tumor grade, stage or size
Chen et al.[220]	2022	30 OSCC patients with recurrence/metastasis vs. patients without recurrence/metastasis	• CES2 was downregulated in OSCC patients, especially those with recurrence or metastasis • CES2 reprogrammed lipid metabolism by hydrolyzing neutral lipid diacylglycerols (DGs) • CES2 reduced membrane structure lipid phospholipids synthesis • Free fatty acids were converted to acyl-carnitines and transferred to mitochondria, inducing ROS accumulation and apoptosis • CES2 suppressed PI3K/AKT/MYC signaling pathways by reducing signaling lipids
Sai et al.[221]	2022	30 OPMDs, 30 OSCC and 30 healthy controls	• Significant decrease in serum TC, LDL and CHO/HDL ratio in OPMD and OSCC groups vs controls • Significant decrease in serum VLDL and TG in poorly differentiated OSCC • Among OPMDs, serum lipid profile was lower in OSMF compared to leukoplakia and OLP • Gradual decrease in serum TC values from stage I to stage IV of OSCC
He et al.[222]	2022	96 OSCC samples	• PLIN2 (lipid droplet marker) mainly expressed in tumor-infiltrating immunocytes (TIIs) • PLIN2 positive patients harbored more cytoplasmic lipid droplets • CD68 + tumor-associated macrophages (TAMs) were the main source of PLIN2 in OSCC • High PLIN2 levels correlated with higher TNM stage and increased postoperative metastasis • High PLIN2 in invasive tumor front independently predicted shorter metastasis-free survival • High PLIN2 in microenvironment induced immune suppression (less CD8 + T cells, more CD68 + TAMs and Foxp3 + Tregs) • PLIN2 positively correlated with immune checkpoint molecules (CSF1R, LGALS9, IL-10, CTLA-4, TIGIT)