In recent years, the landscape of cancer biology has been profoundly transformed by insights into the nuanced regulation of proteins through post-translational modifications (PTMs). PTMs represent a biochemical phenomenon in which small-molecule substrates, such as acetyl-CoA, crotonyl-CoA, butyryl-CoA, and phosphate, are covalently linked to specific amino acid residues on proteins in a reversible and tightly controlled manner. This dynamic modification process is far from trivial, as it governs critical cellular functions by remodeling protein activity, stability, and interactions. The complexity of PTMs is immense, with over 450 distinct forms identified to date, collectively orchestrating a regulatory network indispensable for cellular homeostasis and adaptability.
Within the context of tumorigenesis, PTMs mediated by metabolic substrates—hitherto celebrated examples focusing on histone acetylation—have pivoted attention toward a broader spectrum of ‘acyl’ modifications. These metabolite-derived PTMs are increasingly recognized as pivotal determinants of cancer cell behavior, influencing survival, proliferation, metastasis, and drug resistance. Such modifications fine-tune not only the function of non-histone proteins through direct alteration of enzymatic and structural properties but also modulate chromatin architecture and gene expression patterns by modifying histones, thereby reshaping transcriptional landscapes central to oncogenesis.
Driven by the altered metabolic milieu typical of cancer cells, aberrant levels of metabolites fuel a cascade of unique PTMs. This metabolic dysregulation serves as both a consequence and driver of tumor progression, with metabolic byproducts acting as donors for covalent modifications that can activate oncogenic pathways or suppress tumor suppressor functions. Recent advances have delineated a variety of novel acyl PTMs, such as lactylation, crotonylation, and butyrylation, all contributing distinct regulatory cues. These modifications collectively rewire cellular signaling and epigenetic frameworks, exemplifying a sophisticated interplay between metabolism and protein function that underscores the multifaceted progression of malignancies.
Crucial to the investigation of metabolite-driven PTMs is the mastery of analytical technologies capable of precise and comprehensive detection. Traditional platforms like liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) have established themselves as core methodologies to characterize metabolite profiles within tumor cells. However, challenges persist in detecting metabolites exhibiting strong polarity, structural isomerism, or inherently low ionization efficiencies, thereby hindering a holistic capture of the PTM landscape. To surmount these obstacles, cutting-edge chromatography techniques employing chemical derivatization strategies have emerged. These approaches chemically stabilize target metabolites by connecting them to derivatization reagents, enhancing their ionization potential and chromatographic behavior, thus enabling more sensitive and accurate profiling essential for unraveling PTM-mediated mechanisms in cancer.
The therapeutic implications of targeting metabolite-mediated PTMs in oncology are enticing and increasingly tangible. By focusing on key enzymes involved in the biosynthesis, installation, or removal of aberrant PTMs, researchers aim to thwart the pathological signaling cascades that underpin tumor growth and resistance. For instance, compelling evidence highlights lactylation of the DNA repair protein NBS1 as a driver of chemoresistance through facilitation of homologous recombination. Experimental interventions using LDHA inhibitors, such as stripentol, or genetic ablation of LDHA substantially reduce NBS1 lactylation, bolstering chemotherapy sensitivity. This exemplifies how precision targeting of metabolic-epigenetic crosstalk can potentiate existing cancer therapies and overcome refractory disease states.
Beyond pharmacologic inhibition, innovative molecular tools including cell-penetrating peptides and small molecule antagonists offer promising avenues to selectively inhibit pathological PTMs on target proteins. These approaches hold potential not only to modulate cancer cell phenotypes but also to circumvent the off-target toxicities prevalent in systemic enzyme inhibition. The development of these next-generation modulators is grounded in a deepening mechanistic understanding of PTM networks and their cellular consequences, heralding a new era of metabolic-epigenetic interventions tailored to tumor-specific vulnerabilities.
Equally compelling is the recognition that diet and metabolic homeostasis profoundly influence tumor biology by modulating PTMs. Nutritional interventions have emerged as ancillary strategies capable of disrupting acyl modifications conducive to malignancy. For example, dietary restriction of palmitic acid (PA) has been shown to suppress palmitoylation of the oncogenic kinase AKT, effectively impeding liver cancer progression in experimental models. This insight underscores the broader concept that lifestyle and metabolic equilibrium can intersect with molecular oncogenesis via the regulation of PTMs, presenting opportunities for preventive and adjunctive cancer management.
Despite the rapid strides in characterizing acyl PTMs, significant challenges remain. One fundamental obstacle is the low stoichiometry of these modifications, where only a minor subset of the proteome is modified at any given time, presenting difficulties for detection and quantification. Such scarcity demands highly sensitive and robust proteomics workflows to capture these elusive yet functionally critical modifications. Moreover, the diversity of PTMs is continuously expanding, with newly described modifications like alkylation and vitcylation broadening the functional repertoire and complexity of protein regulation in cancer.
Another layer of intricacy arises from PTM crosstalk—where multiple modifications coexist on a single protein and influence each other’s installation or removal. This interdependency creates a regulatory web that governs protein function in a context-dependent manner, complicating mechanistic dissection and therapeutic targeting. To date, most research has focused on isolated PTMs on individual proteins, but future studies must integrate combinatorial PTM landscapes to fully elucidate their biological and pathological significance.
Translating these molecular insights into clinically effective therapies presents its own hurdles. Enzymes responsible for PTM installation or erasure, such as acyltransferases and deacylases, are often challenging drug targets due to their broad substrate specificity and potential systemic side effects. Despite this, preclinical innovations like the lactyl-resistant knock-in mouse model developed to activate innate immunity demonstrate the promise of genetically informed PTM targeting strategies. However, the clinical translatability and generalizability of such interventions require thorough validation and optimization to ensure safety, efficacy, and applicability across diverse tumor types.
Looking forward, the convergence of metabolomics, proteomics, and epigenetic research holds immense promise for revealing previously unrecognized mechanisms by which metabolites drive tumor progression via PTMs. Advanced techniques and integrative analyses will refine our understanding of the metabolic-epigenetic interface, paving the way for novel biomarkers and therapeutic targets. Harnessing this knowledge could revolutionize cancer diagnosis, enable precision therapeutics, and inform preventative strategies grounded in metabolic modulation.
Ultimately, the burgeoning field of metabolite-mediated PTMs invites a paradigm shift in oncology, expanding the frontiers beyond genetic and epigenetic mutations to encompass the dynamic chemical modifications that define cellular identity and fate. By deciphering the language of acyl modifications, scientists are opening new avenues toward conquering cancer’s complexity, ushering in a future where tumor metabolism is not merely a hallmark of disease but a linchpin for its control and eradication.
Subject of Research: Metabolite-mediated post-translational modifications in cancer cells and their implications for tumor progression and therapy.
Article Title: Acyl post-translational modification of proteins by metabolites in cancer cells.
Article References:
Wang, X., Guo, Y., Fu, Y. et al. Acyl post-translational modification of proteins by metabolites in cancer cells.
Cell Death Discov. 11, 247 (2025). https://doi.org/10.1038/s41420-025-02535-4
Image Credits: AI Generated
