TABLE 3.

Metabolite‐based biomarkers for OSCC.

Author/Year	Source of biomarkers	Method	Sample size	Metabolites	Findings
Rodríguez‐Molinero et al. 217	Saliva	Systematic review	3883	L‐Fucose	Increased levels in OSCC compared to Control;
				Glycine, proline, citrulline, ornithine, 1‐octen‐3‐ol, hexanoic acid, E‐2octenal, heptanoic acid, octanoic acid, E‐2‐nonenal, nonanoic acid, 2,4‐decadienal, 9‐undecenoic acid, 3‐Heptanone, 1,3‐Butanediol, 1,2‐Pentanediol, 1‐Hexadecanol, Putrescine, cadaverine, thymidine, adenosine, 5‐aminopentoate, hippuric acid, phosphocholine, glucose, serine, adrenic acid, Choline, BBCA, urea, 3‐hydroxybutyric acid, Pipecolate, Sadenosylmethionine,	Significantly different levels in OSCC compared to Control; There is still a need for more studies, with a larger sample size.
				Ethanol, 2‐Pentanone, phenol, Hexadecanoic acid, Undecane, 1‐octanol, Butyrolactone, benzyl alcohol	Decreased levels in OSCC compared to Control
Grootveld et al. 87	Saliva	Review	N/A	1‐methylhistidine, 2‐oxoarginine and γ‐aminobutyryl‐lysine l‐homocysteate, polyamines (amino acid metabolism); 2‐phosphoglycerate (carbohydrate metabolism); pseudouridine (nucleotide biosynthesis pathway); 4‐nitroquinoline‐1‐oxide, ubiquinone and reduced glutathione (oxidative stress pathway); choline, S‐adenosylmethionine and methionine (quaternary amine metabolism); BCAAs (TCA cycle, BCAA degradation); urea (urea cycle); and the ketone bodies 3‐D‐hydroxybutyrate and hydroxy‐isovalerate (lipid metabolism)	Perturbations pathways involved in the metabolism of amino acids, proteins, carbohydrates and nucleic acids throughout multistage carcinogenesis developments
Panneerselvam et al. 88	Saliva	Review	N/A	N/D	Establishing standard operating procedures for the use of saliva samples is mandatory. An effective screening system should be developed by combining conventional and modern technologies.
Patil & More 77	Saliva	Review	N/A	Glutathione, polyamines, branched chain amino acids, S‐adenosylmethionine, pipecolate, choline, glycine, proline, inositol 1,3,4‐triphosphate, indole‐3‐acetate and ethanolamine phosphate, urea, 3‐hydroxybutyric acid, pseudouridine, D‐glycerate‐ 2‐ phosphate, 4‐nitroquinoline‐ 1‐ oxide, ubiquinone and estradiol valerate	Increased in OSCC compared to Control; Carcinogenesis causes disturbances in the metabolism of carbohydrates, proteins, amino acids and nucleic acids
Vitório et al. 104	Saliva, serum, plasma and tissue	Review	N/A	Alanine, choline, leucine, isoleucine, glycyl‐leucine, glutamic acid, 120.0801 m/z, phenylalanine, alpha‐aminobutyric acid, serine, indole‐3‐acetate, ethanolamine phosphate, s‐adenosylmethionine, pipecolate, choline, betaine, pipecolinic acid, propionylcholine, lactic acid, acetone, acetate, putrescine, aspartic acid, glutamate, proline, aspartic acid	Increased in OSCC compared to Control
				Ornithine, o‐hydroxybenzoate, ribose‐5‐phosphate, l‐carnitine, acetylphenylalanine, sphinganine, phytosphingosine, s‐carboxymethyl‐l‐cysteine, phenylalanine, valine, l‐leucine, glutamine, 6‐hydroxynicotinic acid	Decreased in OSCC compared to Control
Ishikawa et al. 74	Saliva	CE‐TOF‐MS	72	Proline, carnitine, 5‐hydroxylysine, 3‐methylhistidine, adenosine, inosine, and N‐acetylglucosamine Multivariate analysis: 3‐methylhistidine and 5‐hydroxylysine	Only 3‐methylhistidine found to be a significant prognostic factor
Tantray et al. 76	Saliva	GC–MS	90	Decanedioic acid, 2‐methyloctacosane, octane, 3,5‐dimethyl, pentadecane, eicosane, hentriacontane, 5, 5‐diethylpentadecane, nonadecane, oxalic acid, 6‐phenylundecanea, l‐proline, 2‐furancarboxamide, 2‐isopropyl‐5‐methyl‐1‐heptanol, pentanoic acid, and docosane	Increased in OSCC compared to OPMD and Control
Supawat et al. 79	Saliva	NMR	25	Tyrosine, tryptophan, unk1, unk3, trimethylamine N‐oxide and glycine	Increased in OSCC compared to Control
de Sá Alves et al. 78	Saliva	GC–MS	68	Malic acid, methionine, maltose, protocatechuic acid, inosine, pantothenic acid, dihydroxyacetone phosphate, hydroxyphenylatic acid, galacturonic acid, indole‐3‐acetic acid, uracil, isocitric acid, ribose‐5‐phosphate, o‐phospho serine, lactitol, gluconic acid, hippuric acid, 3‐hydroxypropionic acid and spermidine	Increased in OSCC compared to Control
				Lactose, catechol, 2‐ketoadipic acid, leucine, urea, maleic acid, palmitic acid, ornithine, margaric acid, sucrose, octadecanol, threitol, acetoacetic acid, methionine sulfone, phosphoric acid, elaidic acid, mannose, sorbitol, citric acid, and 3‐aminopropanoic acid	Decreased in OSCC compared to Control
Song et al. 83	Saliva	CPSI‐MS	373	Putrescine, cadaverine, thymidine, adenosine and 5‐aminopentoate	Increased in OSCC compared to Control
				Hippuric acid, phosphocholine, glucose, serine and adrenic acid	Decreased in OSCC compared to Control
Ishikawa et al. 80	Saliva	CE‐TOF‐MS	60	Trimethylamine N‐oxide, putrescine, creatinine, 5‐aminovalerate, pipecolate, N‐acetylputrescine, gamma‐butyrobetaine, indole‐3‐acetate, N1‐acetylspermine, 2′‐deoxyinosine, ethanolamine phosphate and N‐acetylglucosamine	Increased in OSCC compared to OPMD
				N‐acetylhistidine and o‐acetylcarnitine	Decreased in OSCC compared to OPMD
Ishikawa et al. 81	Saliva	CE‐TOF‐MS	48	Ornithine, carnitine, arginine, o‐hydroxybenzoate, N‐acetylglucosamine‐1‐phosphate, and ribose 5‐phosphate	Decreased in OSCC compared to OPMD
Shigeyama et al. 218	Saliva	GC–MS	74	Ethanol, 2‐pentanone, phenol, hexadecanoic acid, disappeared undecane, 1‐octanol, butyrolactone and benzyl alcohol and newly produced 3‐heptanone, 1,3‐butanediol, 1,2‐pentanediol and 1‐hexadecanol	Decreased in OSCC compared to Control
Sridharan et al. 219	Saliva	UPLC‐QTOFMS	61	D‐glycerate‐2‐ phosphate, estrone‐3‐glucuronide, 4‐nitroquinoline‐1‐oxide, sphinganine‐1 phosphate, 1‐methyl histidine, inositol 1,3,4‐triphosphate, d‐glycerate‐2‐phosphate, 2‐oxoarginine, norcocaine nitroxide, pseudouridine, galactosphingosine, and ubiquinone	Increased in OSCC compared to OPMD
Taware et al. 220	Saliva	HS‐SPME‐GC–MS	59	1,4‐dichlorobenzene, 1,2‐decanediol, 2,5‐Bis1,1‐dimethylethylphenol, propanoic acid (ethyl ester), E‐3‐decen‐2‐ol, acetic acid, propanoic acid, ethyl acetate, 2,4‐dimethyl‐1‐heptene, 1‐chloro‐2‐propanol, 1‐chloro‐2‐butanol, 2‐propenoic acid, 2,3,3‐trimethylpentane, ethanol, and 1,2,3,4‐tetrachlorobutane	Increased in OSCC compared to Control
Mikkonen et al. 84	Saliva	NMR	75	Fucose, glycine, methanol, proline and 1,2‐propanediol.	Increased in HNSCC compared to Control, except proline
Lohavanichbutr et al. 85	Saliva	NMR and LC–MS/MS	194	Glycine, proline, ornithine and citrulline	Decreased in OSCC compared to Control
Ohshima et al. 86	Saliva	CE‐TOF‐MS	43	Choline, p‐hydroxyphenylacetic acid and 2‐hydroxy‐4‐methylvaleric acid, valine, 3‐phenyllactic acid, leucine, hexanoic acid, octanoic acid, terephthalic acid, γ‐butyrobetaine and 3‐(4‐hydroxyphenyl)propionic acid, isoleucine, tryptophan, 3‐phenylpropionic acid, 2‐hydroxyvaleric acid, butyric acid, cadaverine, 2‐oxoisovaleric acid, N6,N6,N6‐trimethyllysine, taurine, glycolic acid, 3‐hydroxybutyric acid, heptanoic acid, urea and alanine	Increased in OSCC compared to Control, except Urea
Kamarajan et al. 102	Saliva, Plasma and Tissue	UPLC‐MS/MS for profiling; GC–MS and PCR for validation	Tissue – 103; Saliva – 75; Plasma ‐ 14	Glutamine and glutaminase	Confirmed involvement of glutamate and glutaminolysis. Exogenous glutamine induced stemness via glutaminase, whereas inhibiting glutaminase suppressed stemness in vitro and tumorigenesis in vivo
Ishikawa et al. 82	Saliva and tissue	CE‐TOF‐MS	68	3PG, pipecolate, spermidine, Met, SAM, 2AB, Trp, Val, hypoxanthine, Gly‐Gly, trimethylamine, N‐oxide, guanine, guanosine, taurine, choline, cadaverine, Thr.	Increased in OSCC compared to Control
Zuo et al. 93	Serum	UHPLC‐Q‐Orbitrap HRMS	103	Succinic acid, arginine, 9‐decanoylcarnitine, asparagine‐valine, glutamine, hypoxanthine, sphingosine, and palmitoyl ethanolamide	Increased in OSCC compared to Control
				Hexanoylcarnitine, orotic acid, uric acid, vanillyl mandelic acid, ethyl acetate, and thromboxane B2	Decreased in OSCC compared to Control
Tsai et al. 100	Plasma, urine, and tissue	NMR	110	Creatine, creatine phosphate, glycine, and tyramine	Downregulated in OSCC (Plasma)
				Aspartate, butyrate, carnitine, glutamate, glutathione, glycine, glycolate, guanosine, and sucrose	Upregulated in OSCC (Tissue)
				Alanine, choline, glucose, isoleucine, lactate, leucine, myo‐inositol, O‐acetylcholine, oxypurinol, phenylalanine, pyruvate, succinate, tyrosine, valine, and xanthine	Downregulated in OSCC compared to Control (Tissue)
Wu et al. 92	Serum	UHPLC‐QE‐MS	Discovery: 60 Validation: 77	Serine and lactic acid	Increased in OSCC compared to Control; enhanced diagnostic efficacy when combined
Li et al. 91	Plasma	UHPLC/Q‐Orbitrap HRMS	194	Decanoylcarnitine, cholic acid, cysteine, uridine, taurine, glutamate, citric acid and lyso‐phosphatydilcholine	Decreased in OSCC compared to Control and OPMD.
Sridharan et al. 94	Serum	Q‐TOF‐MS	71	Estradiol‐17‐beta‐3‐sulfate, L‐carnitine, 5‐methylthioadenosine, 8‐hydroxyadenine, 2‐methylcitric acid, putrescine, and estrone‐3‐sulfate, 5,6‐dihydrouridine, 4‐hydroxypenbutolol glucuronide, 8‐hydroxyadenine, and putrescine	Increased in OSCC and OPMD compared to Control
Zhang et al. 221	Tissue	GC–MS	40	Nicotinamide N‐methyltransferase	Increased in OSCC and fibroblast‐like cells compared to Control, but absent in tumor‐infiltrating lymphocytes
Yang et al. 95	Tissue	GC–MS	180	Glutamate, aspartic acid, and proline	Increased in OSCC compared to Control
Paul et al. 99	Tissue	NMR	180	1,3‐Dihydroxyacetone, 2‐oxoglutarate, 4‐aminobutyrate, acetate, adenine, alanine, asparagine, aspartate, betaine, carnitine, choline, creatine, ethanol, fumarate, glucose, glutamate, glutamine, glycine, guanidoacetate, histidine, homocysteine, inosine, isoleucine, isopropanol, lactate, leucine, lysine, methanol, methionine, o‐acetylcarnitine, o‐phosphocholine, phenylalanine, serine, taurine, threonine, tyrosine, uracil, valine, myo‐inositol, sn‐glycero‐3‐phosphocholine, linoleic acid, MUFA, SFA, triglyceride, total fatty acids, and free fatty acids	Upregulated in OSCC compared to Control, except glucose
Yoshimura et al. 101	Tissue	IHC	22	Glucose‐6‐phosphate and lactic acid	Upregulated in OPMD and OSCC
Musharraf et al. 97	Tissue	GC–MS	51	(6E)‐2,6‐Dimethyl‐2,6‐octadiene, 2‐Methyl‐4‐keto‐pentan‐2‐ol, 4‐Hydroxybenzaldehyde, cis‐p‐Menthan‐3‐one, geraniol formate, and stearic acid	Increased in OSCC compared to Control
				Glycine, threonine, glutamine, lysine, proline, alanine, glutamic acid, leucine, serine, 3‐heptanol, ethylene glycol, melibiose, and urea	Decreased in OSCC compared to Control
Ogawa et al. 98	Tissue	CE‐TOF‐MS	64	Lactate, Fum, Mal, Glu, Gly, Asp, Pro, Cys, Hyp, creatinine, putrescine, AMP, GTP, GDP, GMP	Increased in OSCC compared to Control
				Glucose, 3PG, 2PG, creatine, adenylate and guanylate energy charge	Decreased in OSCC compared to Control
Chen et al. 222	Cell line	GC–MS	N/A	Glyoxylate and dicarboxylate, fructose, malate, serine, alanine, sorbose, and glutamate.	Glyoxylate and dicarboxylate increased in OSCC compared to Control
Tripathi et al. 223	Cell line	NMR	N/A	Acetate, alanine, aspartate, AXP, choline, creatine, fumarate, glutamate, glutamine, glutathione, glycerophosphocholine, glycine, histidine, isoleucine, lactate, leucine, lysine, myo‐inositol, N‐acetyl‐aspartate, phenylalanine, phosphocholine, phosphocreatine, proline, pyruvate, taurine, threonine, tryptophan, tyrosine, UDP‐sugars, valine	Alterations of phosphatidylcholine/lysophosphatidylcholine and phosphocholine/glycerophosphocholine ratios, and elevated arachidonic acid in HNSCC; Dysregulation in multiple metabolic events, including Warburg effect, oxidative phosphorylation, energy metabolism, TCA cycle anaplerotic flux, glutaminolysis, hexosamine pathway, osmo‐regulatory and antioxidant mechanism

Abbreviations: N/D, not disclosed; N/A, not available.