Can we treat acne by turning down sebum?

Oral isotretinoin can sharply reduce the amount of oil the skin produces. That makes it an effective acne treatment, but it also requires careful medical supervision. Could a laser or a different tablet target the same glands?

This article was inspired by a LinkedIn essay from dermatologist and physician-scientist Seth Orlow, MD, PhD. Looking back over 26 years, he traced what happened when researchers tried to suppress sebum without the risks and restrictions of isotretinoin. Several ideas worked well enough in the lab to reach clinical trials. Getting a visible improvement in acne proved harder.

Two approaches have brought that question back into focus. A laser heats the glands that make sebum, while an experimental drug called denifanstat blocks an enzyme cells use to make fatty acids.

How does sebum contribute to acne?

Sebaceous glands release sebum, the skin’s natural oil, into hair follicles. Sebum helps maintain the skin barrier and plays a role in the skin’s defences.

Acne develops when several processes overlap:

• The glands produce more sebum, or the composition of that sebum changes.
• Dead skin cells build up inside the pore.
• Inflammation develops.
• The activity of Cutibacterium acnes, a bacterium that normally lives on the skin, also plays a role.

That’s why two people with equally oily skin can have very different acne. It also explains the limits of cleansing. A cleanser can remove surface oil for a while, but scrubbing harder can irritate the skin while the glands continue to produce sebum.

Why isotretinoin is different

Topical retinoids, which you apply to the skin, help keep pores clear and prevent new blackheads and whiteheads. Oral isotretinoin also shrinks sebaceous glands, sharply reduces sebum and affects inflammation.

In small studies, sebum production fell by around 80% or more during a course of isotretinoin. In one study, it rose again after treatment but was still below its starting level a year later. That lasting effect may help explain why some people stay clear for a long time after a course.

The 2024 American Academy of Dermatology guidelines strongly recommend isotretinoin for severe acne, acne causing scars or significant emotional or social distress, and acne that persists despite standard treatment.

It requires medical supervision. Isotretinoin can cause severe harm to a developing fetus, so pregnancy prevention is essential for anyone who can become pregnant. Dry lips and skin are common, and clinicians may check liver enzymes and blood lipids.

Why promising drugs failed in acne trials

Two topical drugs tried to reduce oil production by blocking enzymes involved in making skin lipids. Olumacostat glasaretil showed promise in an early trial but missed its main goals in two phase 3 studies, and development stopped. XEN801 targeted a different enzyme and failed to show a benefit over the inactive gel in its phase 2 trial.

A plausible target is only the beginning. The drug still has to reach the right cells inside the gland at a high enough concentration. Even then, only a clinical trial can show whether changing what happens inside the gland makes a meaningful difference to someone’s acne.

Can a laser reduce sebaceous gland activity?

Two newer laser systems use a wavelength of 1726 nanometres that is readily absorbed by lipids in sebaceous glands. The aim is to heat and damage the glands while cooling the surrounding skin.

In a study of just over 100 people with moderate to severe acne, participants received three sessions. Among those assessed a year later, about two thirds had clear or almost clear skin. The study included a range of skin tones. Mild redness and swelling were common after treatment, and the researchers reported no blistering or changes in pigmentation.

The key limitation was the lack of a comparison group. Everyone received the laser, and some participants missed the one-year assessment. A controlled trial would help show how much of the improvement came from the laser and how it compares with standard treatment.

In practice, laser treatment requires several clinic visits. Sessions can be uncomfortable, and patients often pay out of pocket.

What is denifanstat?

Denifanstat is an experimental tablet that blocks fatty acid synthase (FASN), an enzyme cells use to make fatty acids. Researchers are testing whether blocking it can reduce the fats that go into sebum and also reduce inflammation. Because the tablet acts throughout the body, longer-term safety is part of the question.

In a peer-reviewed phase 2 trial in China, 180 people with moderate to severe acne took one of three doses or a placebo for 12 weeks. At the middle dose, total spots fell by about 61%, compared with 34% with placebo. The difference on the overall acne severity scale was statistically inconclusive.

What did the phase 3 trial in China find?

The larger trial randomly assigned 480 adults with moderate to severe acne to take denifanstat or placebo once a day. The table shows the results the developers reported after 12 weeks.

¹ Participants also had to improve by at least two grades on the acne severity scale. The other rows show how much spot counts fell from the start of the trial.

According to the sponsor-reported results, the larger trial showed an improvement on the overall acne severity scale as well as in spot counts. How denifanstat compares with isotretinoin remains an open question.

What do we know about longer-term safety?

In the 12-week phase 3 trial, the overall rate of adverse events was similar in the two groups. Dry skin and dry eyes were among the side effects reported with denifanstat.

Half of the original participants joined an extension in which everyone received denifanstat. Those who started on the drug could take it for up to a year. The developers reported continued improvement during treatment. Dry skin and dry eyes were the most common treatment-related side effects, and no serious adverse events were judged related to the drug.

With no placebo group in the extension, it’s harder to tell which events the drug caused. The study also leaves two practical questions open. How often do rarer side effects occur, and how long does acne stay better after treatment ends?

A separate year-long trial in people with a liver disease called MASH found that hair loss was more common with denifanstat, affecting about one in five people taking it. That study adds context, but the rate in people treated for acne may differ.

What will the US trial test?

The US phase 3 trial, AURORA, began in October 2026. It aims to enrol around 800 adults and adolescents, with some followed for a year to collect longer-term safety data.

AURORA treats the change in blackheads and whiteheads as one of its three main outcomes, alongside overall treatment success and the change in inflamed spots. The Chinese trial assessed blackheads and whiteheads as a secondary outcome. Denifanstat is still under study for acne.

What this means if you have acne now

If acne is painful, leaving scars or affecting daily life, there are established treatments worth discussing now. The choice depends on what’s on your skin and what you’ve already tried.

• What does your acne look like? Blackheads and whiteheads, inflamed spots and deep, painful nodules can call for different treatment approaches.
• What has already helped? Tell your clinician which treatments you used, for how long and how consistently.
• What else shapes the decision? Mention scarring, hormonal patterns, pregnancy plans and the effect acne has on your daily life.

For mild or moderate acne, clinicians often combine topical treatments that work in different ways, such as a retinoid and benzoyl peroxide. Hormonal treatments may help some people. If oral antibiotics are used, guidelines recommend limiting their duration and combining them with topical treatment to reduce antibiotic resistance. Severe, scarring or persistent acne may warrant a discussion about isotretinoin.