Association of Periodontitis and Hepatocellular Carcinoma: a Systematic Exploratory Review

DISCUSSION

This scoping review systemically mapped and synthesized the available human evidence regarding the association between periodontitis and HCC. Although the current evidence is limited and heterogenous, it increasingly supports a potential association between these two diseases. However, the biological mechanisms underlying this association remain poorly understood, highlighting the need for mechanistic research to assess causality and clarify the exact role of periodontitis in HCC carcinogenesis.

Epidemiological and Genetic Evidence

At the epidemiological level, existing evidence is conflicting. Jordao’s study demonstrated that self-reported poor oral health was a significant site-specific risk factor for HCC. This association persisted after adjusting for confounders and was particularly pronounced among smokers, suggesting that periodontal inflammation may potentially amplify the carcinogenic effects of other known exposures.²² This synergistic pattern, where periodontitis adds to systemic disease risk, has also been reported in other chronic inflammatory conditions and cancers.^27,28

In contrast, Nwizu’s study reported no substantial association between self-reported history of periodontal disease and incident HCC among postmenopausal women.²⁵ We believe discrepancies between these two studies could stem from substantial methodological differences —particularly in participant demographics and how periodontitis and HCC were defined—, highlighting the need for additional rigorous, large-scale prospective research using standardized clinical examinations.

Recent mendelian randomization analyses by Sergeeva et al.,²⁹ found no significant genetic evidence supporting a causal relationship between periodontitis and HCC risk, further fueling the ongoing debate. The authors proposed that human gastric acidity may act as a natural barrier to bacterial translocation from the oral cavity to the gutliver, as experimental data show P.g has minimal activity below pH 2.5.²⁹ However, these results should be interpreted with caution since:

(i) the analysis was limited to populations of European ancestry, reducing generalizability; and (ii) Mendelian randomization captures only inherited genetic risk, overlooking environmental exposures such as oral or gut dysbiosis, which may still contribute to hepatocarcinogenesis independently of host genetic susceptibility.

Clinical and Experimental Insights into HCC progression and severity

Beyond incidence risk, clinical data from Tamaki et al.,²¹ study indicate that periodontitis may exacerbate HCC severity. Periodontal probing depth —an indicator for periodontal disease severity— was significantly and independently associated with more advanced JIS scores and higher levels of circulating ROS in HCC patients.²¹

These findings suggest that while periodontitis may not be a universal contributor to hepatocarcinogenesis, it may function as a site-specific modulator of HCC severity and progression in certain vulnerable populations. Animal models further support this biological plausibility. Sakamoto et al.,³⁰ found that odontogenic infection with P.g in high-fat diet mice significantly increased neoplastic nodule formation (p=0.0188) and HCC incidence (33.3% versus 8.3%) compared to low-fat diet controls. Moreover, immunohistochemistry confirmed the translocation of P.g from the oral cavity to both non-neoplastic and HCC liver tissues, with activation of oncogenic signaling pathways.³⁰

Based on their observations, the authors proposed two biological mechanisms linking periodontitis and HCC: (i) P.g infection activates the integrin β1-FAK/AKT signaling pathway in hepatocytes, promoting cell survival, proliferation and migration while inhibiting apoptosis; and (ii) P.g infection increases the production of TNF-α-mediated inflammation, fostering a ROS-rich microenvironment that promotes liver DNA oxidation enabling carcinogenesis. This was supported by significantly increased levels of 8-OHdG in P.g-infected mice (p=0.0029), a genotoxic marker linked to G:C to T:A mutations in cancer.³⁰

Similarly, the Stelic Animal Model (STAM) by Ohno et al.,³¹ showed that STAM mice with induced periodontitis developed more aggressive forms of NASH-related HCC than periodontally healthy counterparts, exhibiting more advanced vacuolar degeneration and a greater number of visible liver tumors. Histological and molecular analyses further revealed that the periodontitis group had significant upregulation of key inflammatory and tumor-promoting mediators, including TNA-α and angiopoietin-like protein 2 (ANGPTL2). Notably, ANGPTL2 levels were elevated in both the periodontal tissues and serum of periodontitis-induced mice, supporting the notion that inflammatory mediators produced from chronically inflamed periodontal tissues can enter the circulation, reach the liver, and contribute to a pro-inflammatory microenvironment that promotes HCC.

Microbial dysbiosis and the Oral-Gut-Liver Axis

Alterations in the gut microbiome have been implicated in the onset of chronic liver diseases and HCC, while emerging evidence suggests that oral microbiome dysbiosis—often driven by periodontitis—plays an important upstream role.^31,32 Periodontitis disrupts the healthy oral ecosystem, replacing it with pathogenic anaerobes that trigger chronic inflammation and periodontal tissue destruction.³³This dysbiosis is coupled with ulceration of the gingival epithelium, enabling oral bacteria and their byproducts to enter the bloodstream and promote sustained low-grade systemic inflammation.⁶

Furthermore, oral bacteria can be transferred enterally through salivary transplants, potentially contributing to gut dysbiosis and increased intestinal permeability.³⁴ This now “leaky gut” enables bacterial translocation through the portal vein into the liver, where they may interact with hepatocytes triggering inflammation.³⁴ Building on this mechanistic framework, three of the included studies used 16S rRNA sequencing to characterize microbial shifts in HCC and NASH/MASH-related HCC patients.^21, All reported significantly reduced salivary alpha diversity and enrichment of specific pathogens in HCC and NASH/MASH-related HCC individuals c,ompared to controls, including Cyanobacteria, F.n, and P.g. Interestingly, oral Cyanobacteria emerged as an independent risk factor for HCC,^21, a finding most likely due to its ability to produce hepatotoxic and tumor-promoting microcystins.²¹ et al.,²¹

Significantly higher F.n levels were found in both saliva and feces of NASH/MASH-related HCC patients,^23,24 supporting its central role in the oral-gut-liver axis. Mechanistically, F.n may promote carcinogenesis by evading immune responses through the recruitment of myeloid-derived suppressor cells, which impair the anti-tumor activity of cytotoxic T cells and natural killer cells.³⁶ It may further facilitate tumor progression and metastasis through its FadA adhesin, activating the E-cadherin/β-catenin pathway and upregulating methyltransferase-like protein 3 METTL3 expression.³⁶ Beyond the included studies, additional mechanistic literature identifies specific microRNAs as shared regulatory hubs linking periodontitis and HCC. Fan et al.,¹⁹ demonstrated through bioinformatic analysis and tissue validation that the non-coding RNA MIAT acts as a central mediator, as it was significantly upregulated in periodontitis and associated with increased HCC cell proliferation, invasion, and immune escape. This regulatory framework is further characterized by the IncRNA MIAT/hsa-miR-155-5p/CTHRC1 and MIAT/hsa-miR-205-5p axes, where high expression correlates with poor clinical HCC outcomes.¹⁹

Notably, F.n and P.gmay influence these pathways favoring pro-carcinogenic environments. F.n has been shown to upregulate methyltransferase-like protein 3 (METTL3), interacting with hsa-miR-155-5p networks to promote colorectal cancer metastasis,³⁷ whereas P.g inhibits hsa-miR-205-5p expression, activating JAK/STAT signaling in periodontal and liver tissues, facilitating periodontal inflammation and tumor growth/invasion.^19,38 In-vitro evidence supports the inflammatory and hepatosteatotic potential of P.g. Ding et al.,³⁹ demonstrated that human HepG2 hepatocytes exposed to P.g-derived lipopolysaccharides (LPS) accumulated significantly more intracellular lipids than hepatocytes treated with Escherichia coli–derived LPS or untreated controls.³⁹ This was accompanied by increased secretion of pro-inflammatory cytokines (interleukin (IL) -1, IL-8, and TNF-a), and enhanced expression of MyD88 with phosphorylation of p65 and JNK. Notably, silencing p65 and JNK significantly reduced lipid accumulation,³⁹ suggesting that P.g-derived LPS may trigger steatotic and inflammatory changes in hepatocytes, mirroring key features of HCC and NASH/MASH-related HCC. Clinical relevance of elevated salivary P.g in NASH-related HCC patients in Takuma et al.,²³ research was further highlighted by significantly higher serum immunoglobulin G (IgG) antibody titers in this group compared to controls.

Authors found this to be consistent with a history of chronic infection, suggesting a plausible role of periodontitis as a chronic reservoir for the microbial and inflammatory drivers of hepatocarcinogenesis.²³ Functional oral-fecal microbial analyses showed that salivary P.g altered the gut microbiota composition, increasing Lactobacillus and Streptococcus abundance.²⁴ This shift was accompanied by a reduction in short-chain fatty acid (SCFA)-producing bacteria, including Bacteroides and Butyricicoccus.²⁴ This is important as SCFA producers have strong anti-inflammatory40 and anti-tumorigenic effects,⁴¹ and their depletion may foster gut-liver axis dysfunction, exacerbating liver inflammation and carcinogenesis.

Oxidative Stress as a Shared Pathogenic Mechanism

Over 90% of HCC arise in the context of chronic liver inflammation, a condition characterized by sustained oxidative stress and excessive production of ROS. Oxidative stress is a well-established driver of carcinogenesis, as it promotes genomic instability, induces DNA damage, and activates pro-tumorigenic signaling pathways.⁴² Periodontitis has similarly been shown to increase circulating levels of ROS and disrupt the systemic pro-oxidant/antioxidant balance. Importantly, periodontal treatment has been associated with significant reductions in ROM levels and partial restoration of redox homeostasis, indicating that oxidative stress generated in periodontal tissues may have systemic effects, potentially damaging distant organs like the liver.⁴³

Clinical evidence from Tamaki et al.,²¹ supports this systemic link, demonstrating that HCC patients with periodontitis had significantly higher circulating levels of ROMs compared to periodontally healthy HCC individuals (Table 2). Conversely, the authors did not find significant intergroup differences in serum total antioxidant capacity, suggesting that periodontitis may contribute to hepatocarcinogenesis primarily by increasing the oxidative insult rather than by compromising the host’s antioxidant capacity.²¹ These results partially align with prior animal and clinical evidence, in which periodontitis increased the circulatory levels of ROS, but also diminished hepatic glutathione (GSH) and other antioxidant enzymes.^44,47 Notably, some of these animal models have shown that periodontitis induces liver steatosis and fibrosis in rats,47,48 which are hallmark features of fatty liver diseases (like NASH and MASH) and recognized risk factors for HCC.

Study Limitations

The findings of this review should be interpreted with caution due to several intrinsic limitations. As a scoping review, the goal was to map available human evidence on the association of periodontitis and HCC rather than establish definitive causality. Despite a comprehensive search, only a small number of studies met the inclusion criteria (n=6), and inconsistencies in outcome measures (e.g., self-reported oral health status vs objective clinical periodontal examinations) precluded meta-analysis.

Methodological and clinical heterogeneity across studies further limits generalizability, with populations ranging from specific demographics such as postmenopausal women in the United States, to broader adult cohorts in the United Kingdom and Japan. Microbiological analyses were also limited in scope, often focusing on a narrow range of oral and fecal bacteria. Finally, in line with the JBI’s guidelines, no formal risk-of-bias assessment was performed.