Post-translational modifications in hepatocellular carcinoma: Linking senescence, metabolic reprogramming, and immune evasion for therapeutic innovation

Table 1 Major post-translational modification classes linking senescence regulation to immune features in hepatocellular carcinoma

PTM class	Key regulators/substrates (examples)	Primary senescence axis	Immune/TME-relevant effect	Evidence in HCC (typical)	Translational implication	Ref.
Ubiquitination/deubiquitination	MDM2-p53; NEDD4-PTEN; USP family	Checkpoint control (p53/pRb), senescence escape	Shapes antigen presentation and myeloid/T-cell balance via p53–inflammation and PI3K-AKT signaling	Strong mechanistic; clinical links mainly correlative	Target E3/DUBs to stabilize p53 and sensitize to ICI or senolytics	[141-143]
SUMOylation/deSUMOylation	SUMO1/2/3; PIAS; SENP enzymes	Stress signaling; transcription factor activity	Can promote immune evasion through TF reprogramming and inflammatory signaling	Mechanistic; limited prospective clinical validation	SENP/PIAS modulation as an immuno-sensitizing adjunct	[144,145]
Acetylation/deacetylation	p300/CBP; SIRT1/2; HDACs	p53 activity; chromatin accessibility; SASP tuning	Controls inflammatory transcription and exhaustion programs (NF-κB, STATs)	Strong in vitro/in vivo; growing clinical correlative data	HDAC/SIRT targeting to balance senescence induction vs chronic SASP; combine with IO	[146-148]
O-GlcNAcylation	OGT/OGA; YBX1; c-Myc (examples)	Metabolism–chromatin coupling; senescence tolerance	Links nutrient state to immune suppression (myeloid bias, T-cell dysfunction)	Emerging mechanistic; early clinical correlative signals	OGT/OGA inhibition to disrupt metabolic tolerance and recondition TME	[149-151]
Histone lactylation	Lactate; p300; H3K18 La (marker)	Epigenetic remodeling of senescence and stemness programs	Promotes pro-tumor inflammation and immune suppression in lactate-rich niches	Emerging; evidence largely preclinical/omics	Target lactate production/transport or lactylation writers in combination regimens	[152,153]
Histone/non-histone methylation	EZH2; SETD2; KMT/KDM enzymes	Stable chromatin states; senescence maintenance/escape	Regulates antigen presentation and myeloid polarization via epigenetic programs	Mechanistic + correlative cohorts; limited intervention trials in HCC	Epigenetic therapy to restore immune visibility and constrain senescence escape	[154-156]

PTM: Posttranslational modification; TME: Tumor microenvironment; HCC: Hepatocellular carcinoma; MDM2: Mouse double minute 2 homolog; p53: Tumor protein p53; NEDD4: Neural precursor cell expressed developmentally downregulated protein 4; PTEN: Phosphatase and tensin homolog; USP: Ubiquitin-specific protease; pRb: Retinoblastoma protein; PI3K: Phosphoinositide 3-kinase; AKT: Protein kinase B; E3: E3 ubiquitin-protein ligase; DUB: Deubiquitinating enzyme; ICI: Immune checkpoint inhibitor; SUMO: Small ubiquitinlike modifier; PIAS: Protein inhibitor of activated signal transducer and activator of transcription; SENP: Sentrin/small ubiquitin like modifier-specific protease; TF: Transcription factor; p300: Histone acetyltransferase p300; CBP: CREB-binding protein; SIRT: Sirtuin; HDAC: Histone deacetylase; SASP: Senescence-associated secretory phenotype; NF-κB: Nuclear factor-κB; STAT: Signal transducer and activator of transcription; IO: Immunotherapy; OGT: O-GlcNAcylation transferase; OGA: O-GlcNAcase; YBX1: Y-box binding protein 1; c-Myc: Cellular myelocytomatosis oncogene; H3K18 La: Histone H3 lysine 18 lactylation; EZH2: Enhancer of zeste homolog 2; SETD2: SET domain containing 2; KMT: Lysine methyltransferase; KDM: Lysine demethylase.