Evaluation of hepatic sonic hedgehog protein expression in the diagnosis of metabolic dysfunction-associated steatohepatitis

Table 1 Key characteristics and sonic hedgehog homolog-related findings of included original studies

Main research methods	Sample	Key findings related to SHH	Limitations	Ref.
Diagnostic studies	Liver tissue from 100 cases of hepatocellular carcinoma postoperatively	SHH IHC assisted in identifying ballooned cells; combined with hematoxylin and eosin staining resulted in ballooned hepatocyte grading upgrade in 20 cases and downgrade in 0 cases	Single-center design; 2 observers	Kusano et al[41]
Cross-sectional study	69 cases of NAFLD	SHH expression was significantly associated with ballooning degeneration, fibrosis, and M65/M30; moreover, SHH positivity in diabetic patients independently predicted advanced fibrosis	Small sample size and mixed biopsy types	Estep et al[14]
Substudy of clinical trial	59 cases of NASH	Vitamin E treatment resulted in SHH-positive hepatocytes reduction, which was associated with decreased AST levels, reduced ballooning degeneration, and reduced fibrosis	Subgroup analysis sample size was small	Guy et al[38]
Mechanistic clinical and applications	7 cases of NASH and 3 cases of A1AT	Endoplasmic reticulum stress induces SHH production in hepatocytes; the number of SHH-positive cells correlates with fibrosis staging and degree of ballooning degeneration	Small sample size	Rangwala et al[20]
Mechanism, animal model and clinical	16 cases of NAFLD+ animals	HH pathway activation mediates epithelial-mesenchymal transition in ductal cells and promotes fibrosis; fibrosis exacerbates in Ptc+/- mice	Small clinical sample size	Syn et al[25]
Mechanism research	3 cases of NASH+ cells	Ballooned hepatocytes downregulate caspase-9 and induce SHH via c-Jun N-terminal kinase/activator protein-1, forming an autophagic survival pathway	Only 3 clinical samples were available	Kakisaka et al[21]
In vivo	Mouse model	As little as 2%-5% of hepatocytes expressing SHH can induce hepatic fibrosis; SHH promotes the transformation of hepatocellular adenoma into hepatocellular carcinoma	Mouse model; not validated with inhibitors	Chung et al[28]
In vitro model	Human primary hepatocytes + fibroblasts	The 3D cell sheet model successfully induced human ballooned hepatocytes, with SHH secretion increasing by 1.4-2.0 times and myofibroblast activation	Utilizes skin fibroblasts, which are non-physiological	Gao et al[42]
Fundamental research	Mouse + patient serum	SHH promotes NASH via the HSP90β-miR-28-5p axis; serum miR-28-5p can serve as a diagnostic biomarker	SHH tissue staining has not been evaluated	Zhang et al[37]
Clinical intervention	436 cases (subgroup: 120 cases)	Improvement of NASH after bariatric surgery with significant reduction in plasma SHH levels	Non-diagnostic studies	Cabré et al[39]
Clinical + basic	135 cases of NASH+ cells	SHH and TGF-β1 exhibit a positive correlation in NASH (r = 0.6) and are co-localized around ballooned hepatocytes of HSCs	No independent diagnostic data available	Zhou et al[15]
Mechanism research	Mouse cells	The HH signal induces glycolytic reprogramming through HIF1α, driving HSCs activation	SHH has not been validated in NASH models	Chen et al[22]
Mechanism research	db/db mice + cells	Leptin induces SHH expression via PI3K/Akt pathway, activates HH signaling, and promotes HSCs transdifferentiation	The leptin deficiency model cannot fully simulate human conditions	Choi et al[30]
Mechanism research	ob/ob/db/db mouse	Leptin deficiency leads to decreased Smo expression, attenuation of HH signaling, and impaired HSCs activation	Single-gene model, ineffective with exogenous leptin therapy	Xie et al[31]
Mechanism research	Transgenic mice	The HH signal induces HH-induced long non-coding RNA through Gli, which regulates PPARγ via IGF2BP2, thereby influencing hepatic lipid metabolism		Jiang et al[34]
Case-control	38 cases of liver cirrhosis (8 cases of NASH)	SHH levels are significantly elevated in liver cirrhosis without variation across different etiologies; yes-associated protein 1 nuclear translocation is limited	Only 8 cases in the NASH group	Mohagheghi et al[29]
Mechanism research	Mouse + LX-2 cells	The HIF-1α inhibitor AMSP-30m alleviates hepatic fibrosis by inhibiting the SHH pathway; cyclopamine exhibits synergistic effects with AMSP-30m	CCl4 model	Lu et al[36]
Mechanism research	CCl4 rats	Bromelain acid B alleviates hepatic fibrosis by inhibiting the expression of SHH, Ptch1, Smo, and Gli1	Only mRNA was detected, with no protein validation performed	Tao et al[40]
Retrospective cohort	190 cases of MASLD	SHH IHC was used as an adjunct diagnostic tool for MASH; SHH served as an independent predictor (OR = 7.15)	Single-center design, retrospective nature, and wide CI span	Han et al[16]

SHH: Sonic hedgehog homolog; IHC: Immunohistochemistry; NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis; AST: Aspartate aminotransferase; A1AT: Alpha-1 antitrypsin; HH: Hedgehog; Ptc+/-: Patched haploidy deficiency; TGF-β1: Transforming growth factor-β1; HSC: Hepatic stellate cell; HIF1α: Hypoxia-inducible factor 1-α; PI3K: Phosphatidylinositol 3-kinase; Akt: Protein kinase B; Gli: Glioma-associated oncogene homolog; PPARγ: Peroxisome proliferator-activated receptor γ; IGF2BP2: Insulin-like growth factor 2 mRNA-binding protein 2; CCl₄: Carbon tetrachloride; MASLD: Metabolic dysfunction-associated steatotic liver disease; OR: Odds ratio; CI: Confidence interval.