TEHRAN -  Iran’s supreme leader blamed the country’s “enemies” on Tuesday for days of unrest that have seen 21 killed and hundreds arrested in the biggest test for the Islamic regime in years.

The foreign ministry in Tehran also lashed out at US President Donald Trump after his latest Twitter attack on the Iranian authorities over the protests, insisting he should focus on “homeless and hungry people” in his own country.

In a speech carried on state television Ayatollah Ali Khamenei broke his silence on the protests for the first time since they erupted last Thursday. “The enemies have united and are using all their means, money, weapons, policies and security services to create problems for the Islamic regime,” the supreme leader said. “The enemy is always looking for an opportunity and any crevice to infiltrate and strike the Iranian nation.”

A fifth night of unrest Monday to Tuesday saw six protesters killed during an attack on a police station in Qahderijan in the central province of Isfahan, state TV said Tuesday.

At least three other towns near the cultural hub of Isfahan also saw violence overnight, causing the deaths of a young member of the Revolutionary Guards, a policeman and a bystander.

The estimated death toll is now 21 since protests began in second city Mashhad and quickly spread to become the biggest challenge to the Islamic regime since mass demonstrations in 2009.

As violence has grown, authorities have stepped up arrests, with at least 450 people detained in Tehran since Saturday and 100 more around Isfahan on Monday, officials told local media.

President Trump, who has repeatedly criticised Tehran since the latest protests began, praised the demonstrators for acting against the “brutal and corrupt” regime and said Iranians had “little food, big inflation and no human rights”.

Iran’s foreign ministry fired back that the US leader was “wasting his time sending useless and insulting tweets” and advised him to pay more attention to “domestic issues” in his homeland.

The unrest in Iran appears leaderless and focused on provincial towns and cities, with only small and sporadic protests in Tehran as a heavy police presence was reported.

Ali Shamkhani, secretary of the Supreme National Security Council, described the unrest as a “proxy war against the Iranian people” and said online accounts in the United States, Britain and Saudi Arabia are fomenting protests.

A Revolutionary Guards spokesman said the powerful force had not been requested to intervene directly, but insisted officials will “take decisions to finish” insecurity if it persists.

Iran’s reformist politicians condemned the violence and blamed the US for encouraging “troublemakers”, but also called on the authorities to address economic grievances that have fuelled the protests.

“Without doubt the Iranian people are confronted with difficulties in their daily lives... and have the right to peacefully demand and protest,” said a statement from the Association of Combattant Clerics, headed by reformist ex-president Mohammad Khatami.

Moderate President Hassan Rouhani has tried to play down the unrest, which began over economic woes but quickly turned against the regime as a whole with chants of “Death to the dictator”.

In a statement Monday he called them “nothing” and vowed Iranians would deal with “this minority who... insult the sanctities and values of the revolution”.

Pro-regime rallies were held across several towns and cities - reflecting continued support among a large conservative section of society.

The head of Tehran’s revolutionary court, Moussa Ghazanfarabadi, warned that as violence grows punishments for demonstrators would get “heavier”. “We no longer consider them as protesters demanding rights, but as people targeting the regime,” he told the conservative Tasnim news agency.

Rouhani came to power in 2013 promising to mend the economy and ease social tensions, but high living costs and a 12 percent unemployment rate have left many feeling that progress is too slow.

The young are most affected, with as many as 40 percent out of work according to analysts, and rural areas particularly hard-hit.

“People have had enough, especially the young people. They have nothing to be happy about,” Sarita Mohammadi, a 35-year-old teacher in Tehran, told AFP. “The situation is far worse in provinces. Agriculture has been destroyed. I know many who have left the north of the country to come to Tehran to work,” she added.

Rouhani acknowledged there was “no problem bigger than unemployment” in a speech on Sunday, and also vowed a more balanced media and more transparency. Turkey on Tuesday expressed concern about the unrest in a statement that called for “common sense” to “prevail to prevent any escalation”. The European Union on Monday pushed Iran to guarantee the right to protest.

In 2009, authorities ruthlessly put down protests against the re-election of hardliner Mahmoud Ahmadinejad. At least 36 people were killed in 2009, according to an official toll, while the opposition says 72 died.