Table 3.

Summary of proteomic–metabolomic integration studies for PCa within the last decade (2011–2021) ^1,2.

Reference	Experimental Condition	Sample/ n Samples	Analytical Tool for Metabolites	Altered Metabolites (+/−)	Dysregulated Metabolic Pathways	Main Findings
Kopylov et al., 2021 [239]	Schizophrenia-PCa association	52 = PCa	Q-TOF MS UPLC	Cer(d18:1/14:0) 3Cholesta-3,5-dien-7-one 1α,25-dihydroxy-19-nor-22-oxavitamin D312:0 Cholesteryl ester24-hydroxy-cholesterol11-cis-RetinolElaidolinoleic acid14-hydroxy palmitic acid12-amino-dodecanoic acidL-Leucine	Sphingolipid metabolism 3 CholestanoidSteroid biosynthesisSteroid biosynthesis Bile acid biosynthesis Retinol metabolism Linoleic acid metabolismFatty acid biosynthesisFatty acid biosynthesis Valine, leucine and isoleucine degradation	Proteomic and metabolic data → input to approach employing systems biology and one-dimensional convolutional neural network (1DCNN) machine learning. Systems biology + 1DCNN → efficiently discriminate between: Unrelated pathologies = 0.90 (SCZ and oncophenotypes) Oncophenotypes/gender specific diseases = 0.93 (PCa). 1DCNN → high efficiency in PCa diagnosis.
Shen et al., 2021 [240]	Laser-capture-micro-dissection (LCM) androgen quantification	16 = PCa	LC-SRM-MS	Androsterone 4 Androstenedione Dehydroepiandrosterone Testosterone	Interleukin signaling 4 IGF signaling NOTCH4 signaling Wnt signaling PDGF signaling Steroid metabolism ECM signaling, RAF/MAPK signaling by integrins	Coupled parallel LC-MS-based global proteomics and targeted metabolomics → ultrasensitive and robust quantification of androgen from low sample quantity. LC-MS-based method → robust and reliable protein quantification in LCM, including highly accurate profiling of stroma and epithelial LCM of PCa patients.
Teng et al., 2021 [151]	Mast cell (MC) and cancer-associated fibroblasts (CAF) profiling	PCa tissue from prostatectomy patients BPH-1 HMC-1		SAMD14 (+) 5	Immune signaling ECM processes	Transcriptomic profiling of MCs isolated from prostate tumor region → downregulated SAMD14. Proteomic profiling of HMC-1 → overexpression of SAMD14 → modified proteins associated w/ immune regulation and ECM processes. Add HMC-1-SAMD14+ medium to culture of (CAF + prostate epithelium) → reduced deposition and alignment of ECM generated by CAF; suppressed tumorigenic morphology of prostate epithelium.
Blomme et al., 2020 [152]	Androgen receptor inhibitor (ARI)-based LNCaP characterization	LNCaP WT 6 LNCaP bicalut-res LNCaP apalut-res LNCaP enzalut-res	LTQ-OVMS FT-MS QEO-MS LC-MS	Metabolites associated w/ glucose metabolism (citrate, acetyl-coA) and lipid metabolism (+) for DECR1 overexpression Dihydroxyacetone phosphate and glycerol 3-phosphate (−) for DECR1 knockout	Glucose metabolism Fatty acid β-oxidation	2,4-dienoyl-coA reductase (DECR1) knockout → induced ER stress, and stimulated CRPC cells to undergo ferroptosis. DECR1 deletion in vivo → inhibited lipid metabolism, and reduced CRPC tumor growth.
Felgueiras et al., 2020 [238]	PCa-normal prostate differentiation	Tissue: 8 = PCa 8 = normal	FT-IR	Polysaccharide and glycogen (−) Nucleic acid (+)	Lipid metabolism Protein phosphorylation	FT-IR (spectroscopic profiling) and antibody microarray (signaling proteins) → dysregulation in lipid metabolism and increased protein phosphorylation.
Li et al., 2020 [153]	FUN14-domain-containing protein-1 (FUNDC1) silencing	PC3 DU145 C42B	LC-MS UPHLC	AAA+ protease LonP1 Complex V (ATP synthase) TCA intermediates: pyruvate, cis-aconitase, α-ketoglutarate, succinate (−) Glutathione, ROS (+)	TCA cycle Oxidative phosphorylation	FUNDC1 affects cellular plasticity via sustaining oxidative phosphorylation, buffering ROS generation, and supporting cell proliferation. FUNDC1 expression → facilitated LonP1 proteostasis → preserved complex V function and decreased ROS generation.
Dougan et al., 2019 [154]	Peroxidasin (PXDN) knockdown	RWPE1 DU145 PC3 22Rv1 LNCaP	LC-MS-MS	Metabolites that prevent oxidative stress and promote nucleotide biosynthesis (−) (i.e., desirable to increase oxidative stress and decrease nucleotide biosynthesis → apoptosis of PCa cells)	Oxidative stress response Phagosome maturation Eukaryotic initiation factor 2 (eIF2) signaling Mitochondrial bioenergetics Gluconeogenesis I	Increased PXDN expression positively correlated w/ PCa progression. PXDN knockdown → increased oxidative stress and decreased nucleotide synthesis. PXDN knockdown → increased ROS → decreased cell viability, increased apoptosis. PXDN knockdown → decreased colony formation.

¹ The list is non-exhaustive, tabulated as of the writing of this review article. ² Total of 86 queries trimmed down to 7 integrated proteomic–metabolomic PCa studies. ³ Altered metabolite indicates corresponding dysregulated metabolic pathway. ⁴ Enumerated metabolites are presented for quantification purposes using the coupled parallel LC-MS-based global proteomics and targeted metabolomics of LCM. The associated potential biochemical pathways are also listed. These pathways are not dysregulated since there are no experimental conditions applied. ⁵ Tumor-suppressor gene whose protein counterpart potentially induces regulation in immune signaling and ECM processes. ⁶ LCaP cell lines: LNCaP WT = LNCaP wild type; LNCaP bicalut-res = LNCaP bicalutamide-resistant; LNCaP apalut-res = LNCaP apalutamide-resistant; LNCaP enzalut-res = LNCaP enzalutamide-resistant.