Preamble

Energy metabolism is a hub of governing all processes at cellular and organismal levels such as, on one hand, reparable vs. irreparable cell damage, cell fate (proliferation, survival, apoptosis, malignant transformation, etc.), and, on the other hand, carcinogenesis, tumor development, progression and metastazing versus anti-cancer protection and cure. The orchestrator is mitochondria who produce, store and invest energy, conduct intracellular and system-relent signals decisive for internal and environmental stress adaptation, and coordinate corresponding processes at cellular and organismal levels [1, 2]. Consequently, the quality of mitochondrial health and homeostasis is a reliable target for the predictive approach in overall cancer management

  • beginning with health risk assessment at the stage of reversible damage to the health followed by cost-effective personalized protection against health-to-disease transition (primary care of suboptimal health conditions of individuals predisposed to cancer development)

  • and including targeted protection against the disease progression (secondary care of cancer patients against growing primary tumors and metastatic disease) [3].

Indeed, one can discriminate between several bioenergetic phenotypes and metabolic dependencies recently demonstrated for highly heterogeneous group of non-small cell lung cancers (NSCLC) [4]. Accoring to the research evidence presented, mitochondrial networks are organized into distinct subpopulations which in turn govern the bioenergic capacity of corresponding tumors. Further, mitochondrial homeostasis is interrelated with the innate immune sensing and Notch1-AMPK pathway influencing the quantity and characteristics of the pool of cancer stem-like cells. Corresponding mechanisms utilize specifically the hypermitophagy promoting metabolic adaptation and expansion of lung cancer [5]. In consensus, mitophagy is essential for glucose homeostasis and lung tumor maintenance [6], and an induced Pink1-Parkin pathway-mediated mitophagy promotes tolerance to toxic compounds and chemotherapy-resistence in patients with highly aggressive small cell lung cancers [7]. Indeed, dietary intervention is considered highly effective to modulate tumor microenvironment that, in turn, affects metabolism of malignant cells, their growth, and aggressivity in a multi-facted way [8]. On one hand, low glycemic diets may inhibit tumor progression by decreasing blood glucose and insulin levels [9,10,11]. On the other hand, under low nutrient supply in order to obtain nutrients, the malignant cells develop cannibalism in their microenvironment efficiently neutralizing the anti-tumor immune response and indicating poor prognosis in lung cancer [12].

Contextually, a precise metabolic phenoty** based on individualized patient profile is crucial to improve individual outcomes in overall lung cancer prevention and treatments. To this end, all relevant demographic, socioeconomical, clinical, non-clinical, and metabolic parameters have to be considered for individualized patient profile such as described elsewhere for other systemic disorders [13]. Specific clinically relevant phenotypes can be exemplified such as the Flammer syndrome [14]. Flammer syndrome phenotype (FSP) carriers have been described as being predisposed to metastatic disease, once the cancer is clinically manifested [15, 16]. In particular, disturbed microcirculation, psychologic distress, increased sensitivity to various stimuli (stress, drugs, etc.) and altered sense regulation such as pain, smell, and thirst perception, altered sleep patterns, systemic ischemic lesions and low-grade inflammation, low BMI, shifted metabolic profiles as well as frequently reported increased blood endothelin-1 (ET-1) levels, mitochondrial stress, impaired wound healing and existing pre-metastatic niches are characteristic for the FSP and highly relevant for poor individual outcomes of malignant transformation [17, 18]. To this end, systemic inflammatory responses are associated with poor overall survival of lung cancer patients [19]. Also high blood levels of the systemic vasoconstrictor ET-1 are associated with the lung cancer development [20] and poor survival of NSCLC patients—corresponding pahomechanisms are detailed in the literature including increased oxidative stress and cytosolic Ca2+ as well as promoted NSCLC cell proliferation in EGFR- and HER2-dependent manner [21]. Research data demonstrate that endothelin system is decisive for the phenotypic switches in the lung cancer, disease progression, and metastatic promotion [22]. In consensus, a physiologic stabilization of the ET-1 axis was demonstrated in preclinical studies as protective against lung cancer development [23].

Another clinically relevant phenotype is associated with alterations in one-carbon metabolism important for DNA synthesis and methylation. High plasma homocysteine (Hcy) and low folate levels have been associated with lung cancer development and progression [24], among other maliganancies which Hcy detection was suggested to be phenotypically relevant for [25]. Contextually, vitamin 6, 9, and 12 supplements seem to be protective against lung carcinogenesis [26] and supportive for the mental health intervention in treated NSCLC [27]. On the other hand, there are several clearly defined phenotypes in the population which suffer from enhanced Hcy levels in blood and therefore considered a target group to protect against lung cancer predisposition such as individuals

  • with imbalanced diet and insufficient vitamin B 6, 9, and 12 intake

  • diagnosed with disordered one-carbon metabolism

  • diagnosed with obstructive sleep apnea associated with increased Hcy in blood [28], amongst others.

Above exemplified metabolic phenoty** is instrumental for innovative population screening, health risk assessment, predictive multi-level diagnostics, targeted prevention, and treatment algorithms tailored to personalized patient profiles—all are essential pillars in the paradigm change from reactive medical services to 3PM approach in overall management of lung cancers [29]. This article highlights 3PM relevant innovation focused on the energy metabolism as the hub to advance NSCLC management benefiting vulnerable subpopulations, affected patients, and healthcare at large.

Non-small cell lung cancer in focus

As one of the main causes of cancer deaths globally, lung cancer is a significant health burden; thus, the need to understand the mechanisms underpinning the disease progression is imperative [30]. Based on its heterogeneous disease features, lung cancers are classified as small-cell lung carcinoma (SCLC), lung squamous cell carcinoma (LUSC), lung adenocarcinoma (LUAD), and large-cell carcinoma (LCC) [31]. Based on the cancer genome atlas (TCGA) project, there are 299 genes identified and 24 pathways/biological processes that drive the progression of lung tumors. In the recent cancer studies, the oncogenic alterations of the cellular metabolism are now understood as a strong effect, precipitated by the gene changes [32]. Cellular metabolism is associated with cancer driver mutations, and almost two thirds of cancers have glycolytic genes as part of the mutation. The conserved catabolic process that ensures cellular homeostasis as autophagy in lung cancers is an important tumor cell autonomous. The systemic autophagy sustains cancer cell metabolism and promotes immune evasion. Thus, an in-depth knowledge of this autophagy inhibition with its ability for non-tumor recovery is essential in cancer therapy [71].

Protein synthesis

The tumor protein PD-L1 interaction with the immune system is blocked by pembrolizumab thus enabling immune response in various types of cancer [72]. Through epithelial-mesenchymal transition (EMT), miR-607 and calcium-activated nucleotidase 1 (CANT1) pair is key for LUSC therapeutic strategies [73]. Moreover, Rb protein can be used for independent prognostic factors in early-stage NSCLC [74]. The p45 protein is predicted to be associated with malignant transformation via p36cyclinD1 regulation [75]. In the human LSCC line called Ben, parathyroid hormone-related protein (PTHrP) production can be regulated with IL-6-treated cells and PTHrP is influenced by both insulin-like growth factors I and II (IGF-I, IGF-II) [76]. Chemokine receptor CXCR4 induced SDF-1/CXCR4 axis for NSCLC patients may lead to important implications [77]. EpCAM and TROP2 gene overexpressions were found to be correlated with NSCLC [78]. Due to the phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) binding protein (4E-BP1), p-4E-BP1 Thr37/46 had a poor prognostic significance in NSCLC [79].

Squamous cell carcinoma antigen 1 (SCCA1) can sensitize cells to endoplasmic reticulum (ER) stress through the activation of caspase-8 independent of the death receptor apoptotic pathway [80]. The EGFR family member of HER3 blocking antibody, U3-1287/AMG888, when complimented with radiotherapy could reduce cell and tumor growth and thus will increase lung tumor DNA damage and cell death [81]. However, since a study on East Asians and Western populations expressed distinct EGFR gene and protein, histology and staging in NSCLC should be analyzed for any large cohort study [82]. The lack of PIAS3 protein expression post-translational modifications in SCC made PIAS3 a potential therapeutic molecule that will target the STAT3 pathway in NSCLC [83]. Expression of apoptosis blocking bcl-2 protein predicts a poor prognosis for radiation-treated NSCLC patients [84]. Bronchoalveolar lavage (BAL)-exosomal human aspartyl β-hydroxylase (ASPH) is a potential biomarker for NSCLC diagnosis [85].

MicroRNA-26a (miR-26a) as an anti-oncogene regulates tumorigenic properties of EZH2 in human lung carcinoma cells [86]. Moreover, EZH2 can promote tumor progression via regulating VEGF-A/AKT signaling in NSCLC [87]. Src kinase inhibition induced by dasatinib is effective againtst cisplatin resistance [88]. Insulin-like growth factor binding protein-3 (IGFBP-3) with its molecular framework can serve as a new line of antiangiogenic cancer drugs [89]. Fascin actin-bundling protein 1 (FSCN1) and protein tyrosine phosphatase receptor type F (PTPRF) promote tumor progression in LUSC [90]. The CXCL12/CXCR4 produced by Prx1+ mesenchymal cells can be a target to eradicate parenchymal leukemia stem cells (LSCs) in acute myeloid leukemia (AML) [160]. Through mitochondrial membrane depolarization, the proliferation of NSCLC cells is inhibited by Nisin ZP exposure. While this was observed with increased ROS generation on cell lines, an in vivo follow-up study might lead to therapeutic development for NSCLC [165].

Arginine pathway

As one of the most versatile amino acids, arginine serves as a precursor to many molecules such as protein [166]. L-Arginine promotes the interaction of T cells with tumor antigens, and L-arginine plays a key role in the survival and progression of arginine auxotrophic tumors [167]. Circulating L-arginine can predict the lifespan of cancer patients undergoing immune checkpoint inhibitor treatment option [168]. The suppression of tumor cell viability by myeloid lineage to deplete arginine by arginase 1 signals the role played by neutrophil lineage cells [169]. Protein arginine methyltransferase 7 (PRMT7) overexpression promotes metastasis in NSCLC, and this was predicted to be through the interaction with HSPA5 and EEF2 [170]. Through the process of enhancing small cell lung cancer (SCLC) tumor growth, coactivator-associated arginine methyltransferase 1 (CARM1) regulates arginine methylation of Smad7 [171]. Moreover, autophagy inhibitors protect recombinant human arginase (rhArg)-treated NSCLC cells, and thus, rhArg-induced autophagy and apoptosis is anti NSCLC progression [172]. Through influencing arginine synthesis, Aconiti Radix Cocta (ARC) is suggested to be an anti-tumor by regulating the energy metabolism that influence arginine synthesis [173].

Pentose phosphate metabolic pathway

PPP is an essential metabolic pathway that supports the growth and invasion of cancer cells. TP53-induced glycolysis is the main apoptosis regulator (TIGAR) in PPP [174]. MicroRNA (miR)-218 (miR-218) reduced glucose consumption in NSCLC through PPP [175]. PPP-related lncRNAs for NSCLC has an improved detection and treatment based on the different upregulated immune checkpoints in C1 subtype [176]. Moreover, it could identify lncRNA PTTG3P levels associated with cell proliferation NSCLC and thus a new therapeutic and prognostic strategies [177]. PPP-related proteins, NF-E2-related factor 2 (Nrf2) is a prognostic significance and associated with NSCLC histology [178]. The highly oxidative environment of the lung induces controlled stress response pathways. Lung tumors harboring TF nuclear factor erythroid-2-related factor 2 (NFE2L2/NRF2) pathway alterations created questions as to the exploitation of both immune and metabolic features in treating LUSC. It is found that the metabolites identified in the plasma of Keap1f/f/Ptenf/f tumor mice are associated with reprogramming of the PPP [179].

Through PPP, palbociclib reduces the activity of the limiting enzyme, glucose 6-phosphate dehydrogenase. This may target CDK4/6 inhibition with glutaminase inhibitors for NSCLC patients, especially those with RB-proficient tumors [180]. The functional role and regulatory mechanism of keratin 6A (KRT6A) overexpression can increase PPP flux by upregulating glucose-6-phosphate dehydrogenase (G6PD) levels [181]. Xanthatin can attenuate PPP in chemoresistance to cisplatin (DDP) resistance for lung cancer, and induce increased ROS levels and apoptosis. This mechanism can mitigate the DDP-resistant antioxidative capacity [182]. C-C motif chemokine 18 (CCL18), that is M2-tumor-associated macrophages, regulates post-translational modifications in A549 cells via PPP [183]. Loss of KEAP1, a negative regulator of the antioxidant response transcription factor NFE2L2/NRF2, activates the PPP in KRAS-mutant LUAD cancers [184]. Specific energy reprogramming episodes in lung cancers expression metabolic targeted therapy (Table 1) and the energy reprogramming mechanism are sketch as

Table 1 Specific energy reprogramming episodes in lung cancer expression in metabolic targeted therapy
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Summary of blocking common NSCLC metabolic pathways as anti-NSCLC

Glutaminolysis is essential for the proliferation of cancer cells, thus inhibiting glutamine transporter SLC1A5 with almonertinib and/or V9302, and downregulating GLUD1 with OSC is a potential therapeutic approach for NSCLC. For lipid biosynthesis, obstructing ATGL activity via prostaglandin E2-independent manners and GPX4 inhibition which can trigger ferroptosis, an iron-dependent form of necrotic cell death marked by oxidative damage to phospholipid are potential energy pathways for NSCLC therapy. In tumor glycolysis pathway, mutant EGFR promotes metabolic reorganization in NSCLC by increasing aerobic glycolysis and PPP, altering pyrimidine biosynthesis, and increasing monounsaturated fatty acid production. When compared to non-malignant cells, KRAS-mutated NSCLC cells produce higher levels of glycolysis enzymes such as PKM2 and LDHA, indicating changes in glucose metabolism and PPP. ALK rearrangements were linked to increased glucose metabolism in highly metastatic adenocarcinoma morphologies. PC, the enzyme responsible for converting pyruvate to oxaloacetate, was shown to be overexpressed and active in NSCLC tumors. Thus, these molecules can be used as therapeutic target for NCSLC. Under metabolic stress conditions, the LKB1-AMPK pathway is activated. The loss of LKB1 expression can alter mitochondrial dysfunction and energy metabolism of the cells, making it an ideal therapeutic target for NSCLC drug designing. For FAO, ACSL3 inhibition with enhanced MGF can inhibit tumor, metastasis, and angiogenesis. PPP-related proteins, Nrf2 is a prognostic significance and associated with NSCLC histology that regulates the cellular defense against toxic and oxidative insults. Its pathway alterations created questions as to the exploitation of both immune and metabolic features in treating LUSC, thus an important target for lung cancer inhibition (Fig. 2).

Fig. 2
figure 2

Blocking of common NSCLC metabolic pathways as anti-NSCLC. ACSL3, acyl-coenzyme A (CoA) synthetase long-chain family member 3; AMPK-AMP, protein activated pathway; ATGL, adipose triglyceride lipase; EGFR, estimated glomerular filtration rate; GLUD1, glutamate dehydrogenase 1; FAO, fatty acid oxidation; LDHA, lactate dehydrogenase A; NFE2L2/NRF2, nuclear factor erythroid-2-related factor 2; MGF, phytopharmaceutical mangiferin; PMK2, pyruvate kinase isozymes M2; PPP, pentose phosphate pathway; OSC, osmundacetone

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Energy metabolism mechanism exerted by cancer drugs used for NSCLC

MA-CLCE downregulates the expression of PI3K/AKT, a survival signaling regulator that modulates Nrf-2 [213]. DSS inhibits phosphorylation of Akt and ERK1/2 and downregulating Nrf2 expression [214]. Another partially by Nrf2 RNAi knockdown was seen with PR-104, a phosphate ester pre-prodrug that regulates the ARE pathway [215]. A1E inhibits the PI3K/Akt and NF-κB survival pathways and induces cytochrome C release and mitochondrial membrane potential collapse [216]. Through the suppression of caveolin-1/AKT/Bad pathway, miR-204 expression sensitizes cisplatin-induced mitochondrial apoptosis [217]. Furthermore, through NF-κB signaling pathways, Euscaphic acid G treatment inhibits IκBα and IKKα/β phosphorylation thus leading to blockage of NF-κB p65 phosphorylation [218]. Bortezomib, a class I histone deacetylase (HDAC) inhibitor prevents the romidepsin-mediated RelA acetylation and NF-κB activation, and this leads to caspase activation [219]. Triptolide involved NF- κB and toll-like receptors and utilizes IL-17 signaling pathway to regulate immune and inflammatory responses thereby promoting apoptosis to inhibit tumor development [220].

Calotropin (M11) pro-apoptotic activity was observed with mitochondrial apoptotic pathway [221]. Similarly, Punica granatum (PLE) as a safe chemotherapeutic agent is also predicted to cause cell cycle arrest via mitochondria-mediated apoptotic pathway [222]. Moreover, through the activation of the intrinsic mitochondrial pathway, CP-1, an extract from the Coix lachryma-jobi L. var., can inhibit tumor cell proliferation and induce apoptosis [223]. With mitochondrial signaling pathway, silenced GLIPR1 increases apoptosis [224]. Icariin activates the mitochondrial pathway by inhibiting the activation of the PI3K-Akt pathway-associated kinase, Akt [225]. EELDP triggers apoptosis via the NF-κβ pathway through the increase of the Bax-to-Bcl2 ratio leading to mitochondrial membrane potential fall [226].

Upregulation of ER stress induced unfolded protein response (UPR) pathways with Penfluridol. Moreover, the activation of p38 mitogen-activated protein kinase (MAPK) was a key mechanism for penfluridol-induced autophagosome accumulation [227]. With hematopoiesis (AKT, JAK2, and STAT5), NOV-002 activates c-Jun-NH (2)-kinase, p38, and extracellular signal-regulated kinase [228]. Another Akt/MAPK pathway activation was seen with compound 6q in a ROS-dependent manner to induce apoptosis [229]. Tephrosin can induce cancer cell death via the autophagy pathway [230]. It does this via ROS generation and Hsp90 expression inhibition [231]. Rapamycin and 3-BrPA inhibit mTOR signaling and glycolysis probably due to ATP depletion and reduce expression of GAPDH [232]. Downregulating ALDH3A1 by β-elemene can inhibit glycolysis and enhance OXPHOS, thereby suppressing tumors [233]. Through dose-dependently, Bu-Fei decoction (BFD) can suppress EMT induced by TGF-β1 via attenuating canonical Smad signaling pathway [234]. Downregulating survival with erlotinib can result in reversal of erlotinib resistance in EGFR mutation [235]. Gefitinib and osimertinib effects change in amino acids especially at the tyrosine kinase domain [236]. The energy reprogramming mechanism induced by common anti-cancer drugs for NSCLC is summarized in Table 2.

Table 2 The energy reprogramming mechanism induced by common anti-cancer drugs for NSCLC
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Conclusions, expert recommendation, and outlook in the context of 3P medicine

Phenoty** is crucial for advanced primary and secondary care

In both primary and secondary care, phenoty** is crucial for innovative screening programs, identification of vulnerable subgroups in the population (protection against health-to-desease trasition) and individuals affected by an early stage disease for the targeted energy metabolism reprogramming to protect them against the disease progression. Several clinically relevant phenotypes have been described related to mitochondrial stress and shifted energy metabolism such as the Flammer syndrome phenotype [237] with characteristic symptoms and signs including disturbed microcirculation, psychologic distress, altered sleep patterns, low BMI, low blood pressure, systemic ischemic lesions, low-grade inflammation, shifted metabolic profiles as well as frequently reported increased blood levels of systemic vasoconstrictor endothelin-1 (ET-1), mitochondrial stress, impaired wound healing, pre-metastatic niches, and poor individual outcomes, once FSP carriers are diagnosed with cancers [238]. High ET-1 levels in blood are associated on one hand with the FSP [239] and on the other hand with lung cancer development [20] and poor survival of NSCLC patients [21]. FSP is usually manifested early in life; therefore, there is sufficient room for phenoty** and cost-effective measures to protect FSP carriers against cascading pathologies [238, 240].

Another clinically relevant phenotype is associated with elevated homocysteine (Hcy) levels in blood characterized by either mild or severe hyperhomocysteinemia (HHcy) and compromised mitochondrial health and, synergistically with low folate levels, associated with lung cancer development and progression [24]. Therefore, Hcy metabolism is a promising target for predictive diagnostic and health protective approaches in 3P medicine concepts [241].

Contextually, the quality of mitochondrial health and homeostasis is a reliable target for the predictive approach in overall cancer management

  • Beginning with health risk assessment at the stage of reversible damage to the health followed by cost-effective personalized protection against health-to-disease transition (primary care of suboptimal health conditions of individuals predisposed to cancer development)

  • Including targeted protection against the disease progression (secondary care of cancer patients against growing primary tumors and metastatic disease) [1, 3].

Health risk assessment utilizing tear fluid analysis as painless and patient-friendly approach for evaluating mitochondria-related biomarkers to predict systemic diseases has been developed and is commercially available [242].

Breakthroughs on NSCLC energy reprogramming

Inhibiting glutamine transporters, downregulating GLUD1, and knockdown of inhibitors related to glutamine are therpecutive options in energy rewiring treatment options for NSCLC. Obstructing ATGL activity via prostaglandin E2-independent manners, high dose of DEX via M1-like TAMs, and blocking of Nano-DOX-induced PD-L1 via TAM lipid biosynthesis energy reprogramming. PI3K, FGFR1, EGFR, and VEGF/VEGFR signaling and CDK4/6 and KEAP1/NRF2 pathway are key for glycolysis MR in NSCLC. For serine metabolism, LKB1 to LKB1/AMPK signaling and inactivation of STK11/LKB1 lead anti-tumor efficacy in NSCLC. In FAO, ACSL3 inhibition with enhanced MGF and ACADL regulating Hippo/YAP pathway are anti-tumor immunity strategies. In mevalonate pathway, through the RhoA/Rock1 pathway, FPPS mediates TGF-β1-induced cell invasion and blocks EMT process while inhibiting ERK/P90RSK signaling pathway of TIMM50 and Nrf2 expression induce apoptosis are essential for mitochondrial pathway. While CARM1 regulates arginine methylation of Smad7 in tumor proliferation, rhArg and ARC are essential for MR in the arginine synthesis pathway. PPP-related lncRNAs upregulate immune checkpoints in C1 subtype and identify lncRNA PTTG3P levels in glutaminase inhibitors.

Limitations

The role of redox-associated genes in the NSCLC pathogenesis and the critical glycolysis-related lncRNAs are not fully explored. Furthermore, tumor DNA methylation data and TCGA-derived miRNA/mRNA sequencing will give a robust energy metabolism for these cancer subtypes. In addition, radiomic features could not identify clinical and core signaling pathways of LUSC, and the EGFR family member of HER3 blocking antibody could not reduce cell and tumor growth. Combination treatments are not explored with regards MR in these tumor subsets. For instance, SLC1A5 inhibition with almonertinib and/or V9302 could be autophagy inhibition-based therapy in NSCLC. Moreover, conventional therapies such as the CPT system are not fully studied. For the resistance phenomenon, metabolic vulnerability of cisplatin-resistant cancers as a target to nucleoside metabolism is not explored at length.

Inhibition of this ATGL activity via high-throughput sequencing the role GPX4 expression to prevent iron-dependent ferroptosis and IL-17A stimulating angiogenesis via promoting FAO angiogenic vascular disorders are new approaches that requires much attention. In addition, NFE2L2/NRF2 pathway alterations on immune and metabolic features in treating LUSC are unclear. Glycolysis flux with low TCA flux and ATP production, ACT therapy, GRGs, and TF regulatory network for NSCLC are not fully studied. In addition, the role of ARC as an anti-tumor by regulating the energy metabolism that influences arginine synthesis is understudied.

Outlook

In the context of 3PM, MR of NSCLC subtypes has a lot to offer. Although there are some setbacks with regard to establishing biomarkers based on the pathway synthesis, which are highly heterogeneous, there is sufficient room for improvements. For instance, the forms of energy reprogramming studied with various cancers are either monotherapy or combination therapy with limited data output. To this end, the multi-omics approach is expected to provide indication for a robust prediction and targeted treatments. All data must be physiologically evidenced creating reliable patient profiles for treatment algorhithms tailoted to the patient.

(i) Predictive approach

With the MALDI-TOF analysis, the specific proteoforms can predict the patients’ response to ICI therapy for NSCLC based on their intensities of spectral features. In host immunity, proteoform-based diagnostics such as blood-based VeriStrat® proteomic test can accurately predict the response NSCLC patients toward immunotherapy [243]. In complex tumor biology, epithelial cell adhesion molecule (EpCAM) fragment patterns have the potential to reveal cancer-specific changes [244]. The value of validated PEP technology, which is both analytically and robust, will confer efficient diagnosis to NSCLC to explore the source of proteoforms as biomarkers based on its diagnostic potential [245]. Moreover, proteoformic signatures of cancer cellular bioenergetics may serve for prognosis [246].

With proteomic screening, cancer cells switching between energy sources will get stratified between individual subtypes. For instance, the non-glycolysis-related function found a rate-limiting enzyme PFKP as the key regulator in long-chain fatty acid oxidation. This glucose starved-metabolic stress via AMPK pathway will reveal inspirations to other energy sources for tumor growth [247]. The approaches including unsupervised shotgun proteomics with Nanoflow liquid chromatography and high resolution mass spectrometry is capable to identify expressed proteins in relative abundance. This pathway search engine (PSE) may qualify pathways linked to linear energy transfer-induced apoptosis [248] for individualised predictive approach.

(ii) Targeted prevention

The mitochondrial proteomics can reveal invasion abilities in cancers and metastasis, and this has prospects on regulating mitochondrial dynamics [249]. In addition, proteomic analysis is considered a key approach to detect mitochondrial metabolism and energy rewiring thereby preventing the occurrence of metastasis [250]. Based on BMP1 isoforms of NSCLC, the plasma proteoforms revealed distinct differential regulation. Since these isoforms are control-associated, the insights into their mechanism will shed some light on the progress of NSCLC disease progression [251]. The high throughput top-down proteomics (TDP) in an Orbitrap mass spectrometer with its accessible platform will enable proteoforms to be applicable in the preventive medicine [252].

In proteomic analysis, iTRAQ can give isobaric tags for relative, absolute quantitation of mutated genes and TME hypoxia designs for new therapies [253]. When this approach is combined with MALDI-TOF/TOF mass spectrometry analysis and two-dimensional fractionation (OFFGEL/RP nanoLC) could lead not just development of potential treatment options but also biomarker assay for many types of cancers [254]. For instance, with additional data based on proteomics, the study on α-hederin induction of ferroptosis was confirmed to also lead to membrane permeabilization and apoptosis in NSCLC [255]. Protemics has the potential to reveal a number of vulnerable energy stores in biological systems [256]. In addition to dysregulated pathways, proteomic data can reveal cancer associated with adhesion and energy sensing [257].

(iii) Personalized treatments

Protein epitome profiling or epitomics are promising for coprecipitated protein composition and specific posttranslational modification, and while this could classify hypothetical C9 proteoforms in lung cancers, its application is imperative for treatment of NSCLC [258]. The Matrisome DB complete collection data of ECM proteomic will enable the patient to build a comprehensive ECM atlas for targeted therapy [259]. The analysis of proteforms for NSCLC patients after undergoing chemotherapy will reveal plasma protein vitronectin, and this can avert the aftermath consequences [260]. Clinical biobanking and proteoform annotation within chromosome consortia will give an optimal therapeutic strategy for NSCLC [261].

In drug delivery, it is imperative for proteomics to adjuvant the metabolic flux analysis. This will give a robust tumor vascular remodeling and initiate blood vessels to deliver the targeted drugs to the needy cells in the system [262]. Proteomic-based screening of resistance biomarker resistance and mechanisms will lead to tailored therapeutic strategies [263], for instance, in identification of exosomes, which are critical for endosomal compartmentalization. A comparative proteomic analysis could give a wholesome of PKM2 especially in cisplatin resistance in NSCLC [264]. The proteostatic regulation and ubiquitination of intramitochondrial proteins have a lot to reveal for drug sensitivity and resistance based on the role of OXPHOS cancers [265]. Two-dimensional electrophoresis (2DE)-based proteoformic approaches reveal metabolic pathway, intracellular signaling cascade, protein degradation, and transcriptional and translational control for cancer progression [266]. Moreover, delta masses at the proteoformic scale identification will decipher the number of glycolytic enzymes and cancer-specific protein modifications for both precision medicine and also for MR therapeutic options [267]. Figure 3 summarizes corresponding innovation and clinical relevance.

Fig. 3
figure 3

Contributions of energy metabolism pathways to 3PM in NSCLC

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