Differential effects of rice husk-derived liquid smoke on the metabolic viability of HeLa and SHED cells

Efeitos diferenciais da fumaça líquida derivada da casca de arroz sobre a viabilidade metabólica de células HeLa e SHED

Abstract

Rice husk-derived liquid smoke is a biomass pyrolysis product rich in phenolic compounds with reported biological activities. However, its differential effects on cancer cells and stem cells remain insufficiently understood. This study aimed to evaluate the cytotoxic effect of rice husk liquid smoke on HeLa cells and its impact on the viability of stem cells from human exfoliated deciduous teeth (SHED). Rice husk liquid smoke was produced through pyrolysis and diluted with sterile distilled water to obtain working concentrations. HeLa cells were treated with concentrations ranging from 5% to 80%, while SHED cells were exposed to concentrations of 2.5% to 20%. Cell viability was assessed using the MTT assay after 24 hours of treatment. The half-maximal inhibitory concentration (IC₅₀) for HeLa cells was determined using dose–response analysis. Rice husk liquid smoke induced a concentration-dependent reduction in HeLa cell viability, with substantial inhibition observed even at low concentrations. The calculated IC₅₀ confirmed strong cytotoxic activity against cancer cells. In contrast, SHED cells showed greater tolerance to treatment, maintaining viability above 70% across all tested concentrations. Rice husk-derived liquid smoke produced a marked reduction in HeLa cell metabolic viability, whereas SHED cells maintained comparatively higher viability across the tested concentrations. These findings suggest its potential as a natural bioactive agent with relevance in both anticancer applications and regenerative medicine.

Keywords:
liquid smoke; rice husk; stem cells; cancer; HeLa cell

Resumo

A fumaça líquida derivada da casca de arroz é um produto da pirólise de biomassa rico em compostos fenólicos com atividades biológicas relatadas. No entanto, seus efeitos diferenciais em células cancerígenas e células-tronco permanecem insuficientemente compreendidos. Este estudo teve como objetivo avaliar o efeito citotóxico da fumaça líquida de casca de arroz sobre células HeLa e seu impacto sobre a viabilidade de células-tronco de dentes decíduos esfoliados humanos (SHED). A fumaça líquida de casca de arroz foi produzida por pirólise e diluída com água destilada estéril para obter as concentrações de trabalho. As células HeLa foram tratadas com concentrações variando de 5% a 80%, enquanto as células SHED foram expostas a concentrações de 2,5% a 20%. A viabilidade celular foi avaliada utilizando o ensaio MTT após 24 horas de tratamento. A concentração inibitória média (IC₅₀) para as células HeLa foi determinada por meio de análise dose-resposta. A fumaça líquida de casca de arroz induziu uma redução concentração-dependente na viabilidade das células HeLa, com inibição substancial observada mesmo em baixas concentrações. A IC₅₀ calculada confirmou forte atividade citotóxica contra as células cancerígenas. Em contraste, as células SHED apresentaram maior tolerância ao tratamento, mantendo viabilidade acima de 70% em todas as concentrações testadas. A fumaça líquida derivada da casca de arroz produziu uma acentuada redução na viabilidade metabólica das células HeLa, enquanto as células SHED mantiveram viabilidade comparativamente mais elevada nas concentrações testadas. Esses achados sugerem seu potencial como agente bioativo natural com relevância tanto em aplicações anticancerígenas quanto em medicina regenerativa.

Palavras-chave:
fumaça líquida; casca de arroz; células-tronco; câncer; célula HeLa

1. Introduction

Liquid smoke is a product of organic biomass pyrolysis that contains various bioactive compounds, including phenols, carbonyls, furans, and aromatic derivatives (Andy et al., 2021). Rice husk is a particularly attractive raw material for liquid smoke production due to its abundance as an agricultural by-product and its high lignocellulosic content. During pyrolysis, lignin decomposition generates phenolic compounds that have been reported to exhibit antioxidant, antimicrobial, anti-inflammatory, and anticancer activities (Kaur and Ubeyitogullari, 2023).

Rice husk-derived liquid smoke contains methoxyphenol derivatives such as 4-methoxyphenol, 4-ethyl-2-methoxyphenol, and isoeugenol, which are known to inhibit free radical formation and reduce oxidative stress (Arundina et al., 2020; Risfaheri et al., 2025). The biological effects of phenolic compounds are influenced by their concentration, chemical environment, and cellular context. Although these compounds may exhibit antioxidant activity through reactive oxygen species scavenging, they may also interfere with cellular redox balance or mitochondrial function under certain conditions. Therefore, the redox-related effects of rice husk-derived liquid smoke should be regarded as context-dependent rather than exclusively antioxidant (Arundina et al., 2021b; Saputra et al., 2025). These properties suggest potential roles in the regulation of inflammation, cellular proliferation, and survival.

Recent studies have highlighted the regenerative potential of natural bioactive compounds in influencing stem cell behavior. Stem cells from human exfoliated deciduous teeth (SHED) possess strong proliferative capacity and multilineage differentiation potential, making them valuable for regenerative medicine applications (Mohd Nor et al., 2023). Identifying natural agents capable of supporting stem cell viability while maintaining cellular stability is an important objective in tissue engineering.

Conversely, the ability to suppress uncontrolled proliferation remains a central goal in cancer therapy. HeLa cells, a widely used cervical cancer model, provide a useful platform for evaluating the antiproliferative effects of natural compounds (Chunarkar-Patil et al., 2024). Ideally, bioactive agents should inhibit malignant cell growth without severely compromising the viability of normal or regenerative cell populations.

Despite the known biological properties of rice husk liquid smoke, its differential effects on stem cells and cancer cells have not been fully explored. Therefore, this study aimed to evaluate the effect of rice husk liquid smoke on SHED viability and its cytotoxic activity against HeLa cells, in order to assess its potential as a bioactive agent with both regenerative and anticancer relevance.

2. Materials and Methods

2.1. Preparation of rice husk liquid smoke

The rice husk liquid smoke used in the present study was obtained from the same preparation previously described and chemically characterized by Arundina et al. (2021a). The rice husks, identified asOryza sativa, were obtained from a local farmer in Malang, East Java, Indonesia. The liquid smoke was produced at the Forest Products Research and Development Center Laboratory, Bogor, Indonesia.

Rice husk liquid smoke was produced through pyrolysis at 400°C for 8 hours using a pyrolysator reactor. The generated smoke was condensed through a water-cooled condenser system to obtain liquid smoke. Pyrolysis produced three main fractions: liquid smoke, tar, and char.

The condensed liquid smoke was separated and subjected to solvent partitioning by mixing 1000 μL of liquid smoke with 1500 μL dichloromethane (DCM) for 30 minutes to obtain DCM-soluble fraction (organic phase) and Water-insoluble fraction.

For biological testing, the working concentrations of rice husk liquid smoke were prepared by diluting the stock liquid smoke with sterile distilled water. The final concentrations used were 5%, 10%, 20%, 40%, and 80% for HeLa cell treatment and 2.5%, 5%, 10%, and 20% for SHED treatment. A broad concentration range of 5% to 80% was used in HeLa cells to characterize the cytotoxic response across increasing exposures and to support IC₅₀ estimation. In SHED cells, a lower concentration range of 2.5% to 20% was used to evaluate cellular tolerance within a range considered more relevant for cytocompatibility assessment and informed by previous testing of rice husk-derived liquid smoke in non-malignant cells. Because the two cell types were not tested across completely identical concentration ranges, direct comparison was restricted to the overlapping concentrations of 5%, 10%, and 20%.

2.2. Ethical statement

This study received ethical approval from the Ethics Committee of the Faculty of Dental Medicine, Universitas Airlangga, Surabaya (No. 1081/HRECC.FODM/XI/2024).

2.3. HeLa cell culture

HeLa cells were cultured in Dulbecco’s Modified Eagle Medium (DMEM) (Gibco, Thermo Fisher Scientific, USA; Cat. No. 11965-092) supplemented with 10% fetal bovine serum (FBS) (Gibco, Thermo Fisher Scientific, USA; Cat. No. 16000-044), 1% penicillin–streptomycin (Gibco, Thermo Fisher Scientific, USA; Cat. No. 15140-122) and 1% fungizone (Gibco, Thermo Fisher Scientific, USA; Cat. No. 15290-018). Cells were incubated at 37°C in a humidified atmosphere with 5% CO₂. Culture medium was replaced every 2–3 days. Cells were passaged upon reaching 80–90% confluence using trypsinization.

2.4. SHED isolation and culture

Stem cells from human exfoliated deciduous teeth (SHED) were isolated from extracted primary teeth. Pulp tissue was removed under sterile conditions and digested using 0.25% trypsin for 35 minutes.

The resulting cell suspension was centrifuged and cultured in DMEM supplemented with 20% FBS, L-glutamine (Gibco, Thermo Fisher Scientific, USA; Cat. No. 25030-081), penicillin (100 U/mL) (Gibco, Thermo Fisher Scientific, USA; Cat. No. 15140-122), streptomycin (100 μg/mL) (Gibco, Thermo Fisher Scientific, USA; Cat. No. 11860-038). Cells were incubated at 37°C with 5% CO₂ and subcultured until adequate confluence was achieved.

2.5. Cytotoxicity assay in HeLa cells

HeLa cells were seeded in 96-well plates and treated with rice husk liquid smoke at concentrations of 5%, 10%, 20%, 40%, and 80%. After 24 hours of incubation, cell viability was evaluated using the MTT assay (Thermo Fisher Scientific, USA; Cat. No. M6494). MTT solution (5 mg/mL) was added to each well and incubated for 4 hours. Formazan crystals formed by viable cells were measured using a microplate reader at 540 nm. Cell viability (%) was calculated relative to untreated control cells.

The half-maximal inhibitory concentration (IC₅₀) was determined using dose–response data from the MTT assay. IC₅₀ values were calculated using probit analysis to determine the concentration required to reduce cell viability by 50%.

2.6. SHED viability assay

SHED cells were seeded in 96-well plates and treated with rice husk liquid smoke at concentrations of 2.5%, 5%, 10%, and 20%. After 24 hours, cell viability was assessed using the MTT assay under identical conditions as described for HeLa cells.

2.7. Statistical analysis

All experiments were performed in triplicate, and data are presented as mean ± standard deviation (SD). Statistical analysis was conducted using one-way analysis of variance (ANOVA) to compare differences between control and treatment groups. Post hoc multiple comparison testing was performed to assess group-specific differences. A p-value of < 0.05 was considered statistically significant.

For cytotoxicity analysis in HeLa cells, the half-maximal inhibitory concentration (IC₅₀) was calculated from the dose–response curve using probit analysis to determine the concentration required to reduce cell viability by 50%.

3. Results

3.1. Cytotoxic effect on HeLa cells

The cytotoxic activity of rice husk-derived liquid smoke was evaluated in HeLa cells across a concentration range of 5–80%. Cell viability analysis revealed a pronounced concentration-dependent inhibitory response (Figure 1).

Figure 1
Effect of rice husk-derived liquid smoke on HeLa cell viability. HeLa cells were treated with increasing concentrations of rice husk liquid smoke (5–80%), and cell viability was assessed relative to untreated control cells. Treatment induced a significant concentration-dependent reduction in cell viability. Even at low concentration (5%), liquid smoke markedly decreased cell survival, while higher concentrations (10–80%) resulted in near-complete inhibition. Data are presented as mean ± SD. All treated groups were significantly different from control (****p < 0.0001).

Untreated control cells maintained approximately 100% viability, whereas exposure to liquid smoke resulted in a substantial reduction in cell survival even at the lowest tested concentration. Treatment with 5% liquid smoke reduced viability to approximately 20%, indicating strong cytotoxic activity at low exposure levels.

Further reductions were observed with increasing concentrations. At 10%, cell viability decreased to below 10%, while treatments at 20%, 40%, and 80% reduced viability to minimal levels, approaching near-complete inhibition. Statistical analysis showed that all treated groups differed significantly from the control (p < 0.0001).

Notably, the most pronounced decline occurred between the control and 5% concentration, suggesting high sensitivity of HeLa cells to rice husk liquid smoke. Increasing concentrations beyond 10% produced only marginal additional reductions in viability, indicating that maximal cytotoxic effect was largely achieved at relatively low doses.

3.2. IC₅₀ determination in HeLa cells

To further quantify the cytotoxic potency of rice husk liquid smoke, the half-maximal inhibitory concentration (IC₅₀) was determined from the dose–response curve (Figure 2).

Figure 2
Determination of IC₅₀ value of rice husk-derived liquid smoke in HeLa cells. A dose–response curve was generated to evaluate the cytotoxic potency of rice husk liquid smoke against HeLa cells. Cell viability decreased progressively with increasing concentrations, enabling calculation of the half-maximal inhibitory concentration (IC₅₀), defined as the concentration required to reduce cell viability by 50%.

Consistent with the observed viability reduction, the IC₅₀ was reached at a relatively low concentration, confirming the strong susceptibility of HeLa cells to treatment. This quantitative measure supports the potent antiproliferative activity of rice husk liquid smoke against cervical cancer cells.

3.3. Effect on SHED cell viability

In contrast to the marked cytotoxicity observed in HeLa cells, SHED cells demonstrated greater tolerance to rice husk liquid smoke exposure. Treatment at concentrations ranging from 2.5% to 20% produced only moderate reductions in viability (Figure 3).

Figure 3
Effect of rice husk-derived liquid smoke on SHED cell viability. SHED cells were treated with increasing concentrations of rice husk liquid smoke (2.5–20%), and cell viability was evaluated relative to untreated control cells. Treatment resulted in a moderate concentration-dependent reduction in viability, with SHED survival remaining above 70% across all tested concentrations. Data are presented as mean ± SD. All treated groups were significantly different from control (****p < 0.0001).

SHED viability remained above 70% across all tested concentrations, with values of approximately 84%, 82%, 76%, and 71% at 2.5%, 5%, 10%, and 20%, respectively. Although statistically significant differences were observed compared to untreated controls (p < 0.0001), the magnitude of reduction was substantially less pronounced than that seen in HeLa cells.

4. Discussion

This study identified differential responses of HeLa and SHED cells to rice husk-derived liquid smoke under the tested experimental conditions. HeLa cells showed a marked reduction in MTT-based metabolic viability, whereas SHED cells maintained comparatively higher viability. Because these cell types differ in tissue origin, phenotype, metabolism, and biological function, the findings represent responses in two distinct cellular contexts rather than direct evidence of cancer-selective cytotoxicity.

HeLa cells showed high sensitivity to treatment, with a substantial reduction in metabolic viability occurring even at the lowest tested concentration. The low IC₅₀ value further indicates the strong cytotoxic effect of rice husk-derived liquid smoke under the present experimental conditions. Phenolic constituents of liquid smoke, including guaiacol, mequinol, and related compounds, may exert different redox effects depending on their concentration, chemical environment, and the biological characteristics of the target cells.

Previous studies have reported that phenolic compounds may act as antioxidants by scavenging reactive oxygen species under certain conditions, whereas under other conditions they may disrupt mitochondrial activity or alter cellular redox homeostasis ((Gazzano et al., 2018; Gorlach et al., 2015). Therefore, the possible involvement of oxidative stress in the response of HeLa cells is a literature-based interpretation rather than a mechanism demonstrated in the present study. Because intracellular reactive oxygen species, mitochondrial function, and apoptosis-related markers were not directly evaluated, the reduction in HeLa cell viability cannot be conclusively attributed to a pro-oxidant mechanism (Arfin et al., 2021; Brandl et al., 2025).

In contrast, SHED cells demonstrated greater tolerance to liquid smoke exposure, particularly at lower concentrations. The preservation of cell viability in SHED suggests that the bioactive constituents may exert a dual effect depending on concentration. At low levels, certain components such as fatty acid derivatives, including oleic acid, may contribute to maintaining stem cell viability and supporting cellular stability. Oleic acid has been reported to regulate stem cell behavior and promote proliferative signaling through activation of transcription factors such as TLX, which play roles in cell cycle regulation and tissue regeneration (Jiang et al., 2017; Kandel et al., 2022). At higher concentrations, however, the reduction in SHED viability indicates that the same bioactive compounds may shift from a supportive to an inhibitory role. This concentration-dependent response aligns with previous observations that phenolic compounds and unsaturated fatty acids can exhibit biphasic effects, promoting survival at low doses but inducing cytotoxic stress at higher exposures.

The differential response between HeLa and SHED cells may be related to intrinsic differences in cellular metabolism, proliferation, and stress-response mechanisms (Liu et al., 2025). Cancer cells and stem cells differ in their metabolic requirements and regulation of redox homeostasis, which may influence their responses to complex mixtures of phenolic compounds. Nevertheless, these mechanisms were not directly assessed in the present study, and the observed difference between HeLa and SHED cells should therefore be interpreted as a cell-type-dependent response rather than evidence of a specific redox pathway.

Rice husk-derived liquid smoke contains multiple bioactive constituents, including guaiacol, phenolic derivatives, and fatty acids, which may collectively contribute to the observed biological effects (Arundina et al., 2021a; Kim et al., 2011; Surboyo et al., 2021). Phenolic compounds have been reported to display antioxidant or pro-oxidant properties depending on their concentration and experimental context. Because the present study evaluated only MTT-based metabolic viability, it was not possible to determine whether antioxidant activity, oxidative stress, mitochondrial dysfunction, or another mechanism was responsible for the cellular responses (Liu et al., 2023).

The different concentration ranges used for HeLa and SHED cells should also be considered when interpreting the results. HeLa cells were assessed over a broader concentration range to characterize their cytotoxic response, whereas SHED cells were evaluated over a lower range for cellular tolerance. Consequently, direct comparison between the two cell types should be restricted to the overlapping concentrations of 5%, 10%, and 20%. At these shared concentrations, HeLa cells showed a greater reduction in MTT-based viability than SHED cells. Nevertheless, because identical concentration ranges were not used and a formal selectivity index was not calculated, the findings do not establish definitive selective cytotoxicity.

This study has several limitations. Cellular responses were evaluated using only the MTT assay after 24 hours of treatment. Although this assay provides information on cellular metabolic activity, it does not directly distinguish reduced proliferation from cell death or identify the underlying mechanism of cellular injury. Oxidative stress, mitochondrial dysfunction, apoptosis, and cell proliferation were not directly measured. In addition, HeLa and SHED cells do not represent a tissue-matched malignant and non-malignant cell pair. Differences between them may therefore reflect tissue origin, differentiation status, metabolic characteristics, and malignancy status. The proposed redox-related mechanisms are based on previous literature and require confirmation through direct mechanistic studies.

Taken together, rice husk-derived liquid smoke produced different effects on the metabolic viability of HeLa and SHED cells under the tested conditions. HeLa cells showed a marked reduction in viability, whereas SHED cells demonstrated comparatively greater tolerance. These findings support a differential cell-type-dependent response but do not establish cancer-selective cytotoxicity or preservation of stem-cell function. Future studies should use matched malignant and non-malignant cervical cell models, identical concentration ranges, formal selectivity-index calculations, and complementary assays of proliferation, cell death, oxidative stress, mitochondrial function, and stem-cell characteristics.

5. Conclusions

Rice husk-derived liquid smoke produced differential effects on HeLa and SHED cells under the tested experimental conditions. HeLa cells showed a marked concentration-dependent reduction in MTT-based metabolic viability, whereas SHED cells demonstrated comparatively greater tolerance within the evaluated concentration range. Because HeLa and SHED cells represent distinct biological models rather than a tissue-matched malignant and non-malignant cell pair, these findings should not be interpreted as definitive evidence of cancer-selective cytotoxicity or preservation of stem-cell function. Further studies using matched cell models, identical concentration ranges, and complementary mechanistic assays are required to establish selectivity and determine the mechanisms underlying these cellular responses.

Acknowledgements

This research received funding from Directorate of Research and Community Service, Directorate of Research and Development Republic of Indonesia 2025 in the Schema Penelitian Fundamental Reguler (PFR), with funding ID 059/C3/DT.05.00/PL/2025 and 2335/B/UN3.LPPM/PT.01.03/2025.

Data Availability Statement

Research data is available in the body of the article.

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e-mail: [e-mail]

Editor:

Takako Matsumura Tundisi

Publication Dates

• Publication in this collection
  11 Sept 2026
• Date of issue
  2026

History

• Received
  19 Apr 2026
• Accepted
  22 July 2026